CN1134439C - Pyrrolo [2,3D] pyrimidines and their use as tyrosine kinase inhibitors - Google Patents

Pyrrolo [2,3D] pyrimidines and their use as tyrosine kinase inhibitors Download PDF

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CN1134439C
CN1134439C CN98805152.4A CN98805152A CN1134439C CN 1134439 C CN1134439 C CN 1134439C CN 98805152 A CN98805152 A CN 98805152A CN 1134439 C CN1134439 C CN 1134439C
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phenyl
pyrrolo
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pyrimidine
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CN1259950A (en
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D·J·卡德伍德
D·N·约翰斯顿
P·拉弗蒂
H·L·特维格
R·穆斯查肖尔
L·阿诺德
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Abert GmbH & Co. KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compounds of formula (I) including pharmaceutically acceptable salts thereof in which R1 represents hydrogen, 2-phenyl-1,3-dioxan-5-yl, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C5-7 cycloalkenyl group or an (optionally substituted phenyl) C1-6 alkyl group wherein the alkyl, cycloalkyl and cycloalkenyl groups are optionally substitued by one or more groups of the formula ORA in which RA represents H or a C1-6 alkyl group provided that a group of the formula ORA is not located on the carbon attached to nitrogen; R2 represents hydrogen, a C1-6 alkyl group, a C3-8 cycloalkyl group, halo, hydroxy, an (optionally substituted phenyl) C1-6 alkyl group, optionally substituted phenyl or R4; and R3 represents a group of formula (a) in which the phenyl ring is additionally optionally substituted and A represents NH, O, NHSO2, SO2NH, a C1-4 alkylene chain, NHCO, NHCO2, CONH, NHCONH, CO2 or S(O)p in which p is 0, 1 or 2, or A is absent and R5 is attached directly to the phenyl ring; and R5 represents optionally substituted phenyl and, additionally, when A is absent R 5 represents a) a phthalimido group optionally substituted by halo or b) a pyrazolylamino group in which the pyrazole ring is optionally substituted by one or more of the following: hydroxy or optionally substituted phenyl; R4 represents a heterocyclic group; are described which are useful in treating proliferative diseases and disorders of the immune system in mammals. Processes to prepare these compounds and pharmaceutical compositions containing these compounds are also described.

Description

Pyrrolo-[2,3D] pyrimidines and they are as the purposes of tyrosine kinase inhibitor
The present invention relates to 4-amino-7H-pyrrolo-[2,3-d] pyrimidines of new replacement, this compounds has therapeutic activity as protein tyrosine kinase inhibitors; The present invention relates to contain the medicinal compositions of these compounds and their preparation method.
Background of the present invention
Protein tyrosine kinase (PTKs) is the enzyme of tyrosine residues phosphorylation specific in the catalytic proteins.The back change of translating of these substrate protein white matters (usually this is as enzyme) is worked as adjusting cell proliferation and activated molecular switch.At the numerous disease state, be included in the disease (autoimmune, allograft rejection and graft versus host disease) that benign and virulent proliferative disease and the incorrect activation of immunity system produced, all observe abnormal PTK activity.It is believed that the compound that selectivity suppresses the PTKs of response can be used as useful therapeutical agent.
In WO96/10028, disclose as protein tyrosine kinase pp60 C-srcThe formula A compound of inhibitor R wherein 1Be aryl, R 2Be hydrogen, low alkyl group or halo, and R 3Be aryl.Among the application WO97/28161 of pending trial, R is disclosed at the same time 1Be cyclic low-grade alkyl or ring-type low-grade alkenyl unsubstituted or that replace, and R 2And R 3Foregoing formula A compound.Among the application WO97/32879 of pending trial, R is disclosed at the same time 1Be the low alkyl group of low alkyl group or replacement, and R 2And R 3Foregoing formula A compound.
In WO96/40686, disclose and be the formula B compound of adenosine kinase inhibitors
Figure C9880515200141
Wherein X is-N or CR 7, R wherein 7Be hydrogen, halogen, low alkyl group, lower alkoxy or S-low alkyl group; Y is-N or-CH; R 1And R 2Independent separately is hydrogen, hydroxyl, alkoxyl group or acyloxy, or R 1And R 2Be all with an independent hydroxy-protective group or with the hydroxyl of an independent dihydroxyl blocking group protection, or R 1And R 2Do not exist, and connecting R 1And R 2Carbon atom between a two key is arranged; R 3Be hydrogen, hydroxyl, low alkyl group or alkoxyl group; R 4Be in particular (a) hydrogen, (b) amino, (c) halogen, (d) hydroxyl, or R 3And R 4Be combined into=O, or the carbon atom that is connected with them is in conjunction with forming volution; R 5Be in particular hydrogen, low alkyl group or amino; And R 6Be in particular low alkyl group, aryl, heteroaryl or heteroarylalkyl.
The present invention's general introduction
The invention provides formula I compound, comprise its pharmacy acceptable salt,
Figure C9880515200142
R wherein 1Be hydrogen, 2-phenyl-1,3-diox-5-base, C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group or be (optional replace phenyl) C 1-6Alkyl, wherein said alkyl, cycloalkyl and cycloalkenyl group are optional by one or more OR AGroup replaces, R ABe hydrogen or C 1-6Alkyl, prerequisite are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, halo, hydroxyl, (the optional phenyl that replaces) C 1-6Alkyl, optional phenyl or the R that replaces 4And R 3Be formula (a)
Figure C9880515200151
Wherein said phenyl ring is also optional to be substituted and A is NH, O, NHSO 2, SO 2NH, C 1-4Alkylidene chain, NHCO, NHCO 2, CONH, NHCONH, CO 2Or S (O) pWherein p is 0,1 or 2, or A does not exist and R 5Be directly connected on the phenyl ring; And R 5Be the optional phenyl that replaces, in addition when A does not exist, R 5For a) by the optional phthalimido that replaces of halo, or b) the pyrazoles ring is by one or more hydroxyls or the optional pyrazolyl amino that replaces of the optional phenyl that replaces; R 4For being selected from the heterocyclic group of thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, indazolyl, each is optionally replaced these heterocyclic groups by one or more following groups: C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, hydroxyl, the optional phenyl that replaces, (the optional phenyl that replaces) C 1-6Alkyl, (the optional phenyl that replaces) C 1-6Alkylthio or (the optional phenyl that replaces) C 1-6Alkoxyl group; Wherein term " the optional phenyl that replaces " means phenyl and is chosen wantonly replacement by one or more following groups: a) C 1-6Alkyl, b) C 1-6Alkoxyl group, c) phenoxy group, d) hydroxyl, e) phenyl C 1-6Alkyl, f) halo, g) formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, (C 1-6Alkoxyl group) carbonyl, 5-hydroxyl-1-phenyl-3-pyrazolyl, or by C 1-6Alkyl, C 1-6The optional benzoyl that replaces of alkoxyl group or halo, h) formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition, i) by the optional phthalimido that replaces of halo, j) phenyl ring is benzo-fused formation naphthyl or k) nitro.In preferred formula I compound: R 1Be C 1-6Alkyl, C 3-8Cycloalkyl or (the optional phenyl that replaces) C 1-6Alkyl, wherein said alkyl and cycloalkyl are optional by one or more formula OR AGroup replaces, wherein R ABe hydrogen or C 1-6Alkyl, prerequisite are OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, halo, hydroxyl, (the optional phenyl that replaces) C 1-6Alkyl, optional phenyl or the R that replaces 4And R 3Be formula (a) Wherein said phenyl ring is optional in addition to be substituted, and A is NH, O, NHSO 2, SO 2NH, C 1-4Alkylidene chain, NHCO, NHCO 2, CONH, NHCONH, CO 2Or S (O) pWherein p is 0,1 or 2, or A does not exist and R 5Be directly connected on the phenyl ring; And R 5Be the optional phenyl that replaces, in addition, when A does not exist, R 5For a) by the optional phthalimido that replaces of halo, or b) the pyrazoles ring is by one or more hydroxyls or the optional pyrazolyl amino that replaces of the optional phenyl that replaces; R 4For being selected from the heterocyclic group of thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, indazolyl, each is optionally replaced these heterocyclic groups by one or more following groups: C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, hydroxyl, the optional phenyl that replaces, (the optional phenyl that replaces) C 1-6Alkyl, (the optional phenyl that replaces) C 1-6Alkylthio or (the optional phenyl that replaces) C 1-6Alkoxyl group; Wherein term " the optional phenyl that replaces " means phenyl and is chosen wantonly replacement by one or more following groups: a) C 1-6Alkyl, b) C 1-6Alkoxyl group, c) phenoxy group, d) hydroxyl, e) phenyl C 1-6Alkyl, f) halo, g) formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, (C 1-6Alkoxyl group) carbonyl, 5-hydroxyl-1-phenyl-3-pyrazolyl, or by C 1-6Alkyl, C 1-6The optional benzoyl that replaces of alkoxyl group or halo, h) formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition, i) by optional phthalimido or the j that replaces of halo) phenyl ring is benzo-fused formation naphthyl.Detailed description of the present invention
Preferred R 1Be C 3-6Alkyl (for example propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl or hexyl), C 3-8Cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group) or C 5-7Cycloalkenyl group (for example cyclopentenyl, cyclohexenyl or cycloheptenyl), wherein said alkyl, cycloalkyl and cycloalkenyl group can be chosen wantonly by one or more hydroxyls and replace, and condition is on the carbon atom that hydroxyl can not be positioned at nitrogen is connected.Preferred R 1Be sec.-propyl, the tertiary butyl, 2-hydroxyethyl, cyclopentyl, neo-pentyl, 2-hydroxycyclopent base, 4-hydroxycyclopent-2-thiazolinyl, 3-hydroxycyclopent base, 2,3,4-trihydroxy-cyclopentyl, 1,3-dihydroxyl third-2-base or 2,3-dihydroxypropyl.
Preferred R 2Be hydrogen or halo (as chloro, bromo or iodo).Preferred R 2Be hydrogen or chloro.
Preferred R 3Be formula (a) Wherein said phenyl ring is optional in addition to be substituted, and A is O, NHSO 2, NHCO or S (O) pWherein p is 0,1 or 2, and R 5Be the optional phenyl that replaces.Preferred A is O or S.Most preferred A is O.
Most preferred R 3Be the 2-Phenoxyphenyl; the 3-Phenoxyphenyl; the 4-Phenoxyphenyl; 4-(thiophenyl) phenyl; 4-(4-methoxyl group phenoxy group) phenyl; 4-(phenyl sulfinyl) phenyl; 4-(phenyl sulfonyl) phenyl; 4-(4-hydroxyphenoxy) phenyl; 4-(phenylsulfonamido) phenyl; 4-(benzamido) phenyl; 4-(4-kharophen phenoxy group) phenyl; 4-(2-nitro-phenoxy) phenyl; 4-(4-amino-benzene oxygen) phenyl; 4-(3-amino-benzene oxygen) phenyl; 4-(2-amino-benzene oxygen) phenyl; 4-(3-kharophen phenoxy group) phenyl; 4-[4-(N-methyl-kharophen) phenoxy group] phenyl; 4-(2-kharophen phenoxy group) phenyl; 4-(2-acetylaminohydroxyphenylarsonic acid 4-nitrophenoxy) phenyl; 4-(3-carboxyl-4-nitrophenoxy) phenyl; 4-(2-carboxyl-4-nitrophenoxy) phenyl; 4-(4-trifluoromethyl-2-nitro-phenoxy) phenyl; 4-benzamido-3-p-methoxy-phenyl; 4-benzamido-3-hydroxy phenyl; 4-phenylsulfonamido-3-p-methoxy-phenyl; 4-phenylsulfonamido-3-hydroxy phenyl; 3-hydroxyl-4-(4-tert.-butylbenzene sulfonamido) phenyl; 4-(2-hydroxyphenoxy) phenyl; 4-(4-chlorobenzoyl amino)-3-hydroxy phenyl; 4-(3-methoxyl group-4-nitrophenoxy) phenyl; 4-(4-methoxycarbonyl-2-nitro-phenoxy) phenyl; 4-(4-carboxyl-2-nitro-phenoxy) phenyl; 4-(5-chloro-2-nitro-phenoxy) phenyl or 4-[4-nitro-2-(2,2-dimethyl propylene amido) phenoxy group] phenyl.
R in one group of preferred formula I compound 1Be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, benzyl or 2-hydroxyethyl; R 2Be hydrogen, methyl, halo, hydroxyl or phenyl; And R 3Be the 2-Phenoxyphenyl, the 3-Phenoxyphenyl, the 4-Phenoxyphenyl, 4-(4-chloro-N-phthalimido)-3-tolyl, 3-chloro-4-(3-chlorophenoxy) phenyl, 4-(4-methylamino-phenyl amino) phenyl, 4-(4-methylamino-phenyl amino)-2-p-methoxy-phenyl, 4-(4-methylamino-benzyl) phenyl, 4-anilino-2-p-methoxy-phenyl, 3-hydroxyl-4-(4-toluyl amino) phenyl, 3-hydroxyl-4-(2-methoxybenzoyl amino) phenyl, 4-(4-chlorobenzoyl amino)-3-hydroxy phenyl, 3-hydroxyl-4-(2-naphthalene sulfonyl amino) phenyl, 3-hydroxyl-4-[4-(tertiary butyl)-phenylsulfonamido] phenyl, 4-[N-(5-hydroxyl-1-phenylpyrazole-3-yl) amino] phenyl or 4-phenyloxycarbonyl amino-3-hydroxy base.
Second group of compound and pharmacy acceptable salt thereof that preferred formula I compound is represented for formula Ib R wherein 1Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group or be (optional replace phenyl) C 1-6Alkyl, wherein said alkyl, cycloalkyl, cycloalkenyl group are chosen wantonly by one or more formula OR AGroup replaces, R ABe hydrogen or C 1-6Alkyl, condition are OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen or halo; R xBe C 1-6Alkyl, C 1-4Alkoxyl group, halo or hydroxyl; R yBe C 1-6Alkyl, C 1-4Alkoxyl group, halo, hydroxyl, nitro or formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, (C 1-6Alkoxy carbonyl or R yBe formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition; And m and n independently are 0,1 or 2.
The substituted radical preferred group of formula Ib compound is listed below.
Preferred R 1Be C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group, wherein said alkyl, cycloalkyl and cycloalkenyl group are optional by one or more formula OR AGroup replaces, R ABe hydrogen or C 1-6Alkyl, condition are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected.More preferably R 1Be sec.-propyl, the tertiary butyl, 2-hydroxyethyl, cyclopentyl, neo-pentyl, 2-hydroxycyclopent base, 4-hydroxycyclopent-2-thiazolinyl, 3-hydroxycyclopent base, 2,3,4-trihydroxy-cyclopentyl, 1,3-dihydroxyl third-2-base or 2,3-dihydroxypropyl.
Preferred R 2Be hydrogen or chloro.
Preferred R xBe hydroxyl or C 1-4Alkoxyl group.Preferred R xBe hydroxyl or methoxyl group.
Preferred R yBe C 1-4Alkyl, C 1-4Alkoxyl group, nitro, kharophen, amino, N-methyl kharophen, carboxyl, hydroxyl or halo.
Preferred m is 0 or 1.Preferred m is 0.
Preferred n is 0 or 1.Preferred n is 0 or 1, and R yBe hydroxyl, amino or kharophen.
Be appreciated that any referred in this group that contains the chain of three or three above atoms represents that chain wherein can be straight or branched.For example, alkyl can be by containing the propyl group that comprises n-propyl and sec.-propyl and comprising the butyl of normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.At this, term " halo " expression fluoro, chloro, bromo and iodo.
Formula I compound can exist with the salt with pharmaceutically acceptable acid formation.The present invention includes this class salt.The example of this class salt comprises hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, acetate, Citrate trianion, fumarate, tartrate [for example (+)-tartrate, (-)-tartrate or their mixture comprise export trade revolve mixture], succinate, benzoate and the salt that forms with amino acid (as L-glutamic acid).These salt can be prepared by method known to those skilled in the art.
Some formula I compound that contains acid substituted radical can exist with the salt with pharmaceutically acceptable alkali formation.The present invention includes this class salt.The example of this class salt comprises sodium salt, sylvite, lysine salt and arginic acid salt.These salt can be prepared by method known to those skilled in the art.
Can there be more than one physical aspect (as different crystal forms) in some formula I compound, and present invention includes each physical aspect (as each crystallized form) and their mixture thereof of formula I compound.
There are more than one crystallized form in some formula I compound and their salt thereof, and present invention includes each crystallized form and their mixture.Some formula I compound and their salt also can exist with solvate forms, as hydrate, and present invention includes every kind of solvate and their mixture.
Some formula I compound may contain one or more chiral centres, and has different optically active forms.When formula I compound contained a chiral centre, there were two kinds of mapping forms in compound, and the present invention includes the mixture of two kinds of enantiomorphs and enantiomorph.Can split enantiomorph by method that those skilled in the art were familiar with, for example by formation can separated (as by crystallization) diastereoisomeric salt, formation can separated (as by crystallization, gas liquid chromatography or liquid chromatography) diastereoisomeric derivative or the selective reaction (as enzymatic esterification) of title complex, a kind of enantiomorph and special enantiomorph reagent or the gas liquid chromatography in chiral environment or liquid chromatography as on chiral support (as combining the silica gel of a chiral ligand) or have chiral solvent.Be appreciated that and use separation method described above, the isolating enantiomorph of desire is converted into another chemical entity, need the step of the required isomeric form of dissociating.Perhaps available optically active reagent, substrate, catalyzer or solvent synthesize specific enantiomorph by the method for asymmetric synthesis, or by asymmetric conversion a kind of enantiomorph are converted into another kind of enantiomorph.
When formula I compound contains more than one chiral centre, can there be the diastereo-isomerism form in it, can separate diastereomer (as chromatography or crystallization process) by the method that those skilled in the art were familiar with, and each enantiomorph of each centering can separate with previously described method.Present invention includes each diastereomer of formula I compound and their mixture.
Special compounds of formula I include the following compounds and pharmaceutically acceptable salts thereof, The appropriate enantiomers, racemates, or other mixtures of enantiomers: 4 - amino -5 - (2 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (3 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino-7 - methyl-5 - (4 - phenoxyphenyl) pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (4 - phenoxy-phenyl) -6 - Phenyl-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino-6 - methyl -5 - (4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino-6 - hydroxy-5 - (4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino-7 - butyl-5 - (4 - phenoxyphenyl) pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - chloro-4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [4 - (4 - methylamino-phenylamino)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [4 - (4 - aminophenyl methyl amino) -2 - methoxy-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (4 - methylamino) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (4 - methyl-benzoyl amino)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (2 - methoxy-benzoylamino)-phenyl]-7 - tert-butyl-pyrrolo And [2,3-d] pyrimidine 4 - amino -5 - [4 - (4 - chloro-benzoyl) -3 - hydroxyphenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (2 - naphthyl) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (4 - tert-butylphenyl) phenyl]-7 - tert-butyl-pyrrolo And [2,3-d] pyrimidine 4 - amino -5 - {4 - [N-(5 - hydroxy-1 - phenyl-pyrazol-3 - yl) amino] phenyl}-7 - tert-butyl- Pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (4 - phenoxy-carbonyl-amino-3 - hydroxyphenyl) -7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [4 - (4 - chloro-N-phthalimido)-3 - methyl-phenyl]-7 - tert-butyl-pyridine Pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (2 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (3 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (2 - methoxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [4 - (3 - methoxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [4 - (2 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (2 - ethoxycarbonyl) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [4 - (3 - ethoxycarbonyl) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [4 - (2 - carbamoyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [4 - (3 - carbamoyloxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [4 - (2 - hydroxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [4 - (3 - hydroxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (3 - methyl - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (2 - methoxy - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (3 - methoxy - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (2 - chloro-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (3 - chloro-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (2 - ethoxy-carbonyl-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - (3 - ethoxy-carbonyl-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - (2 - amino formyl-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - (3 - amino-formyl-4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - (2 - hydroxy - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - (3 - hydroxy - 4 - phenoxy-phenyl) -7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [2 - chloro-4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [2 - methyl -4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [3 - methyl - 4 - (3 - N phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [2 - methoxy - 4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [3 - methoxy - 4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [2 - ethoxy-carbonyl-4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - ethoxy-carbonyl-4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [2 - carbamoyl -4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - carbamoyl -4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [2 - hydroxy-4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (3 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [2 - chloro-4 - (2 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [2 - chloro -4 - (4 - chlorophenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine Pyridine 4 - amino -5 - [3 - chloro-4 - (3 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [4 - (3 - ethyl-phenoxy) -3 - chlorophenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [4 - (3 - formylphenoxy amino) -3 - chlorophenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - chloro-4 - (3 - hydroxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] Pyrimidine 4 - amino -5 - [3 - methyl - 4 - (3 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [3 - methoxy - 4 - (3 - methoxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - hydroxy - 4 - (3 - hydroxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3 - d] pyrimidine 4 - amino -5 - [3 - methyl - 4 - (3 - methoxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [3 - methoxy-4 - (3 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [2 - methoxy - 4 - (3 - methyl-phenoxy)-phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 4 - amino -5 - [2 - methyl -4 - (3 - methoxyphenoxy) phenyl]-7 - tert-butyl-pyrrolo [2,3-d] pyrimidine 7 - tert-butyl-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - tert-Butyl-6 - chloro-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - isopropyl-5 - (4 - phenoxy-phenyl) -7 H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - cyclopentyl-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 5 - (4 - biphenylyl) -7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - neopentyl-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - tert-butyl-5 - (4 - phenylthio-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - tert-butyl-5 - [4 - (4 - methoxyphenoxy) phenyl]-7H-pyrrolo [2,3-d] pyrimidine - 4 - amine 7 - tert-butyl-5 - [4 - (phenyl-sulfinyl)-phenyl]-7H-pyrrolo [2,3-d] pyrimidin-4 - yl Amine 7 - tert-butyl-5 - (4 - benzenesulfonyl-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 4 - [4 - (4 - amino-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] benzene Phenol N-[4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenyl] benzenesulfonamide Amide N-[4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenyl] benzoic Amide N-{4 - [4 - (4 - amino-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] Phenyl} acetamide 7 - isopropyl-5 - [4 - (2 - nitrophenoxy) phenyl]-7H-pyrrolo [2,3-d] pyrimidin-4 - Ylamine 5 - [4 - (4 - aminophenoxy) phenyl]-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4 - Ylamine 5 - [4 - (3 - aminophenoxy) phenyl]-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4 - Ylamine 5 - [4 - (2 - aminophenoxy) phenyl]-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4 - Ylamine N-{3 - [4 - (4 - amino-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] Phenyl} acetamide N-{4 - [4 - (4 - amino-7 - tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] Phenyl}-N-methylacetamide N-{2 - [4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] Phenyl} acetamide N-{2 - [4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] - 5 - nitrophenyl} acetamide 5 - [4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] -2 - Nitrobenzoic acid 2 - [4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] -5 - Nitrobenzoic acid 2 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] ethanol 2 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] cyclopent Alcohol 4 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] cyclopent - 2 - ol 6 - chloro-7 - cyclopentyl-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 5 - (4 - phenoxy-phenyl) -7 - (2 - phenyl-1 ,3 - dioxan-5 - yl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl amine 3 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] cyclopent Alcohol 4 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] cyclopent - 1,2,3 - triol 7 - cyclopentyl-5 - (2 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 7 - cyclopentyl-5 - (3 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 2 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] propan-1 ,3 - Diol 3 - [4 - amino-5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-7 - yl] propan-1 ,2 - Diol N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - methoxy- Phenyl] benzamide N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - hydroxy- Yl] benzamide N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - methoxy- Phenyl] benzenesulfonamide N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - hydroxy- Yl] benzenesulfonamide N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - hydroxy- Yl] -4 - tert-butyl-benzenesulfonamide 7 - cyclopentyl-5 - [4 - (2 - methoxyphenoxy) phenyl] pyrrolo [2,3-d] pyrimidin-4 - yl Amine 2 - [4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] benzene Phenol 7 - isopropyl-5 - [4 - (3 - methoxy-4 - nitrophenoxy) phenyl]-7H-pyrrolo [2,3 - d] pyrimidin-4 - yl amine 4 - [4 - (4 - amino-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] -3 - Nitrobenzoate 4 - [4 - (4 - Amino-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] phenol N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - methoxy- Phenyl] 4 - tert-butyl-benzenesulfonamide 7 - cyclopentyl-5 - [4 - (2 - methoxyphenoxy) phenyl]-7H-pyrrolo [2,3-d] pyrimidine - 4 - amine N-[4 - (4 - amino-7 - cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - hydroxy- Yl] -4 - chlorobenzylamide 5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 5 - [4 - (5 - chloro -2 - nitrophenoxy) phenyl]-7 - isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4 - yl amine and N-{2 - [4 - (4 - Amino-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) phenoxy] -5 - nitrophenyl Yl} -2,2 - dimethyl-propionamide. ...
May there be different tautomeric forms in some formula I compound or exists with different rotamerism things, and the present invention includes every kind of tautomer and/or the geometrical isomer and their mixture of formula I compound.
May there be separable different stable conformation form in some formula I compound.Because reversing of causing of asymmetric single bonded restricted turning effort asymmetric (as because steric hindrance or ring strain), make separable different conformation thing.Present invention includes the conformer of formula I compound and their mixture.
May there be zwitterionic form in some formula I compound, and present invention includes the every kind of zwitterionic form and their mixture of formula I compound.
The present invention also comprises medicinal compositions, and this medicinal compositions contains the formula I compound or its salt and the pharmaceutically acceptable diluent or carrier for the treatment of significant quantity.
After this, formula I compound or its salt represented in term " active compound ".When treatment was used, active compound can be taken orally, rectal administration, parenteral admin or local application, the preferred oral administration.Therefore, therapeutic composition of the present invention can and the medicinal compositions form of any known oral administration, rectal administration, parenteral admin or local application.Employed pharmaceutically acceptable suitable carrier is to know in the pharmaceutical field in this type of medicinal compositions.The weight of the contained active compound of composition of the present invention is 0.1-99%.Composition of the present invention normally is prepared according to unit dosage.The preferred unit dosage of activeconstituents is 1-500mg.The vehicle that uses when these compositions of preparation is the known vehicle of pharmaceutical field.
Preferred composition of the present invention is a composition for oral administration, and for such route of administration, these compositions all are the medicinal forms of being familiar with, for example tablet, capsule, syrup and water-based or oiliness suspension agent.When these compositions of preparation, the vehicle that uses is the known vehicle of pharmaceutical field.In the presence of disintegrating agent (as W-Gum) and lubricant (as Magnesium Stearate), activeconstituents mixed with inert diluent (as calcium phosphate) and by known method pressing mixt, thus the preparation tablet.Can prepare tablet by the method that those skilled in the art are familiar with, so that the release that can continue compound of the present invention.As needs, this class tablet can carry out enteric coating by known method, for example uses the Cellacefate dressing.Similarly, can prepare the capsule (as hard or soft gelatin capsule) that contain active compound and vehicle or not have vehicle by the method for routine, and if desired, available known method provides enteric coating.Tablet and capsule per unit contain 1 to 500mg active compound.Other liquid preparations for oral administration example is included under the existence of non-toxicity suspension agent (as Xylo-Mucine), contains the aqueous suspension agent of active compound and the oiliness suspension agent that contains The compounds of this invention in suitable vegetables oil (as peanut oil) in aqueous vehicles.
Active compound and additional vehicle (or not having vehicle) can be mixed with granule.Patient can directly swallow this granule, or adds appropriate liquid carrier (as water) before swallowing.Granule can contain disintegrating agent (as the pharmaceutically acceptable effervescent that is formed by a kind of acid plus carbonate or supercarbonate) thereby promote that active compound disperses in liquid vehicle.
The composition of the suitable rectal administration of the present invention is the known medicinal forms that is suitable for this type of administration, as the suppository that forms with theobroma oil or polyoxyethylene glycol matrix.
Medicinal compositions also can be according to the pharmaceutical dosage form of known parenteral admin (as water-based and/or aseptic suspension agent of butyrous and/or the sterile solution in suitable solvent, preferably the solvent of opening with patients'blood etc.) bone intestines external administration (as subcutaneous injection, intramuscularly, intradermal injection and/or intravenous injection [as by injection and/or infusion]).The parenteral agent can be by sterilization (as by micro-filtration method and/or use sterilization reagent [as oxyethane]).Can choose the pharmaceutically acceptable auxiliary that in parenteral dosage form, adds following one or more suitable parenteral admins wantonly: local anesthetic, sanitas, buffer reagent and/or their mixture.Parenteral dosage form can be stored in the suitable sterile seal container (as ampoule and/or glass tube vial) stand-by.In order to improve the stability of lay up period, after pouring into container, liquid (as water) is removed in freezing and decompression with parenteral dosage form.
Medicinal compositions can be according to medicinal forms (as sprays, aerosol, spray solution and/or the powder) intranasal administration of known intranasal administration.The dosing system (as aerosol and/or inhalation) that can use those skilled in the art to be familiar with.
Medicinal compositions can be according to medicinal forms (as slow dissolved tablet, Chewing gum, lozenge, lozenge, pastille, gelifying agent, paste, mouth wash shua, irrigation and/or the powder) orally administering (as sublingual administration) of known orally administering.
Topical drug delivery composition comprises matrix, in this matrix pharmaceutically active compounds of the present invention disperseed in case compound closely with skin contact, thereby can be through the skin absorption compound.Medicinal activity compound and topical vehicle such as mineral oil, Vaseline and/or wax (as paraffin or beeswax) and potential transdermal enhancer (as dimethyl sulfoxide (DMSO) or propylene glycol) are mixed, can prepare suitable transdermal composition.Perhaps active compound is dispersed in pharmaceutically acceptable emulsifiable paste or the ointment base.The amount of active compound should be the amount that can discharge the compound of treatment significant quantity during use in the topical formulations, and topical formulations is to be used for skin.
The compounds of this invention also can or be placed on the administration of intravital compound source continuous infusion by an external source (as venoclysis).Endogenous comprise containing remain the storage of implantation of infusion compound, compound can discharge (as by infiltration) continuously, and implant can be (a) liquid, as treat the suspension or the solution of the pharmaceutically acceptable oil of infusion compound [as with the slightly water-soluble derivative form of dodecanoate for example], or (b) solid, treat the form of infusion compound carrier (for example material of synthetic resins or wax) with implantation.Described carrier can be formed for the monomer that contains whole compounds or for a different set of monomer, and each monomer contains part compound to be discharged.The amount of active compound should be the amount that can discharge the compound of treatment significant quantity in long-time in endogenous.
In some preparations, the The compounds of this invention of use may be useful for very small particle (as obtaining by fluid energy mill).
If desired, in composition of the present invention, active compound can be combined with other suitable pharmacological component.
The present invention has also comprised the purposes of formula I compound as a kind of medicine.
Src and Syk family kinase are playing a crucial role aspect the adjusting of immunologic function.Src family generally includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yes, Hck and Blk.Syk family is considered to only comprise Zap and Syk usually.The Janus family kinase is relevant with the transduction of somatomedin, and urges inflammatory cytokines to send signal by some acceptors.Because formula I compound has these kinase whose abilities that suppress one or more, therefore, to keeping and the treatment of autoimmune disorders of allograft, they can bring into play the effect of immunomodulator.Regulate the ability of t cell activation or enhancing inflammatory process by them, these compounds can be used for treating autoimmune disease.Because rejection is (for solid organs, the host is for transplant rejection or to bone marrow transplantation, graft repels the host), the toxicity of transplanting because of the obtainable immunosuppressor of routine is restricted, and will be benefited from a kind of effective medicine that improves therapeutic index.The experiment of gene target has shown the effect of Src in the biology of osteoclast, and osteoclast is responsible for bone resorption.Regulate the ability of Src by them, formula I compound also can be used for treating the hypercalcemia and the migration of treatment bone of osteoporosis, Paget's disease, tumor promotion.
The verified many Tyrosylprotein kinases of people are proto-oncogenes.Karyomit(e) breakage (Itk kinases breakdown point on karyomit(e) 5) if Abl group translocation or truncate other gene (as cKit) of band BCR (Philadelphia karyomit(e)), cause the dysregulation protein that produces with they from former-change oncoprotein into.In other tumour, the formation of tumour is to be subjected to autocrine or the interactional promotion of external secretion part/growth factor receptors.By suppressing these proteinic tyrosine kinase activities, can destroy the process of this disease.Vascular restenosis is the endotheli ocytosis process that PDGF-relies on.In order to prevent this phenomenon, preventative inhibition PDGFr kinase activity may be a kind of effective means.Therefore, the formula I compound that can suppress the kinase activity of c-kit, c-fms, EGFr, BCR, Abl, PDGFr, KDR/Flk-1, Flt-1, tie-1, tie-2 and other acceptor may have the value of the proliferative disease of the benign and tumour of treatment.
Formula I compound or its salt or the medicinal compositions that contains the formula I compound for the treatment of significant quantity can be used to treat benign and proliferative disease and disease of immune system tumour.This class disease comprises that autoimmune disease is (as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, myasthenia gravis and systemic lupus erythematous), psoriasis, the organ-graft refection (repels as kidney, graft versus host disease), the proliferative disease human cancer of benign and tumour is (as lung cancer, mammary cancer, cancer of the stomach, bladder cancer, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, the prostate cancer and the rectum cancer) and leukemia and comprise that unsuitable vascularization disease is (as diabetic retinopathy, because choroidal new vascularization and infantile hemangioma that the macular degeneration relevant with the age produces).In addition, this class inhibitor can be used for treating oedema, ascites and the transudate diseases such as (example comprise mascular oedema and adult respiratory distress syndrome ADRS) that comprises the VEGF mediation.
Compound of the present invention also can be used for preventing above-mentioned disease.
On the other hand, the invention provides the purposes of formula I compound or its salt in drug manufacture, these medicines can be used for treating Mammals (especially human) proliferative disease and/or disease of immune system.
The present invention also provides the method for treatment proliferative disease and/or disease of immune system, and this method comprises the formula I compound of Mammals (especially human) the treatment significant quantity that needs.
Now, will the preparation method of formula I compound be described.These methods have constituted another aspect of the present invention.These methods are preferably carried out under normal pressure.
In temperature is 50-250 ℃ scope, choose wantonly in the presence of a catalyzer (as the 4-Dimethylamino pyridine), make R 1, R 2And R 3As the formula II compound and the methane amide condensation of preceding definition,
Figure C9880515200321
Thereby preparation I compound.
At catalyzer (as palladium (0) compound as Pd (PPh 3) 4) existence under, by making R 1And R 2As preceding definition and R 3Formula I compound and R for bromine or iodine 3Formula III compound R as preceding definition 3B (OH) 2Reaction can preparation I compound.
By using R 1Be alkyl or (the optional phenyl that replaces) C 1-6Alkyl and X is the formula R of leavings group (as halo or tosyloxy) 1X makes R 2And R 3As the formula IV alkylation of preceding definition, Can prepare R 1Be alkyl or (the optional phenyl that replaces) C 1-6The formula I compound of alkyl.
In temperature is 15-250 ℃ scope, preferably in pressurized vessel, make R 1, R 2And R 3As preceding definition and Y is the formula V compound of leavings group (as halo or phenoxy group) and ammonia or ammonium salt (as ammonium acetate) reaction, Thereby preparation I compound.
Make R 1And R 3Formula VI compound as preceding definition
Figure C9880515200333
With halide reagent such as iodination reagent (as N-iodine succimide) or bromide reagent (as N-bromo-succinimide) or chlorination reagent (as N-neoprene imide) reaction, thereby can prepare R 2Formula I compound for chlorine, bromine or iodine.
Make R 1And R 2As preceding definition and Y is amino formula VII compound
Figure C9880515200341
With X be the formula R of leavings group (as chlorine) 5The compound reaction of COX can prepare R 3Be AR 5Formula I compound, wherein A is NHCO.Perhaps making Y is the formula VII compound and the formula R of halo (as chlorine) 5The COX compound reacts and makes product and ammonia react obtain formula I compound.When A is NHSO 2The time, can use similar method.
Make R 1And R 2As preceding definition and X is halogenated formula VIII compound
Figure C9880515200342
With formula R 5The reaction of OH compound can prepare R 3Be AR 5Formula I compound, wherein A is O.
Make R 1And R 2Formula IX compound as preceding definition
Figure C9880515200343
With formula R 5The reaction of X compound can prepare R 3Be AR 5Formula I compound, wherein A is O.Formula R 5X is a halo in the X compound, preferably has the activatory halo because of another substituting group (as nitro).
Can preparation formula II compound according to the method shown in graphic 1, wherein IPA is a propan-2-ol.
Graphic 1
As the skilled personnel to understand, formula I compound can be converted into other formula I compound by known chemical reactions.For example, the cleavable alkoxyl group obtains hydroxyl, be that amine, amine can be by acidylate or sulfonylations with nitroreduction, and N-acyl compounds hydrolyzable is an amine.By the method that those skilled in the art were familiar with, can be with R 3Be AR 5And wherein A is the formula I compound oxidation of S, and obtaining A respectively is SO and SO 2Formula I compound.
The formula III compound can be prepared available from commerce or by the method that those skilled in the art were familiar with.
Can prepare R according to the method that shows in graphic 2 2Formula IV compound for hydrogen.By the method that those skilled in the art were familiar with, before the step in the end, amido protecting is got up, after graphic 2 final step, go protection then.By similar method, can prepare R 2It or not the formula IV compound of hydrogen. J.Med.Chem?1990， 33?1984
Graphic 2
Perhaps in graphic 2, before the amination, R 3Can be at first by coupling.Perhaps before carrying out any single step reaction, as the substituent R of preceding definition 1Can exist.
Can preparation formula V compound according to the method that shows in graphic 3
Figure C9880515200362
Graphic 3
Can prepare R according to the method that shows in graphic 4 3Formula VI compound for hydrogen.Can be according to J.Med.Chem., 1988,31, method described in 390 and the citation of consulting in the article prepare raw material.By similar method, can prepare R 3It or not the compound of hydrogen.
Figure C9880515200363
Graphic 4
Can make 5-iodine compound coupling preparation formula VII compound with being similar to the described method of preparation formula IV compound.
As skilled in the art to understand, before reacting, be equal to or the substituting group that is similar to adorned functional group in the above method will need protection, after reaction, go protection then.Otherwise the competitive reaction of paying will take place.When perhaps substituting group does not therein disturb, can use above-described another kind of method.For example, at T.W.Green, in " blocking group in the organic synthesis " book that JohnWiley and Sons 1981 are gone out, can find protecting group and their addition that suits and the example of removing method.For example the suitable protecting group of amine is formyl radical or ethanoyl.
By the method for describing in detail below, can measure the vitro efficacy that compound suppresses these Tyrosylprotein kinases.
Suppress Lck or zap70 kinases with respect to the contrast test-compound and make the exogenous enzymes substrate (amount as synthetic peptide Nature.373:536-539 such as () Z.Songyang tyrosine phosphorylation effect is measured the effectiveness of compound by measuring.The expression of ZAP70
The rhabdovirus expression vector that uses as pVL1393 (Pharmingen, Los Angeles, Ca.).The nucleotide sequence of coded amino acid M (H) 6 LVPRGS is placed the 5 ' end in complete ZAP70 (amino acid/11-619) zone of coding.But histidine residues makes this protein of protein affinity purification (vide infra).The LVPRGS bridge is formed the order of an identification to the proteolysis that is undertaken by zymoplasm, makes it possible to remove affinity labelling from this enzyme.Infection multiplicity with 0.5 infects the SF-9 insect cell and results after infecting 24 hours.The extraction of ZAP70 and purifying
With the cracking in damping fluid of SF-9 cell, this damping fluid contains 20mM Tris, and pH8.0,137mM NaCl, 10% glycerol, 1%Triton X-100,1mM PMSF, 1 μ g/ml leupeptin, 10 μ g/ml press down enzyme peptide and 1mM sodium orthovanadate.With on the lysate of solubility in the sepharose HiTrap of chelating post (Pharmacia), make this column equilibration in advance with 50mM HEPESpH7.5,0.3M NaCl.With 250mM imidazoles wash-out fused protein.Enzyme is stored in the damping fluid that contains 50mM HEPES pH7.5,50mM NaCl and 5mM DTT.The source of Lck
The Lck of Lck or brachymemma can be available from commercial (as from (the Saranac Lake of Upstate Biotechnology company, N.Y) and Santa Cruz Biotechnology (the Santa Cruz of company, Ca.) get), or use conventional method by known natural source or the reorganization source is refining obtains.Analyze
(Current Protocolsin Immund., John Wiley and Sons, 11.4.1-11.5.6 page or leaf .1995) described in the scheme front that is used to measure tyrosine kinase activity.Briefly, all reactions are all containing 50mM MOPSO pH6.5,2mM MnCl 2, 5mMDTT, 0.1%BSA, 2-200 μ M ATP, 30-200 μ M peptide, 5%DMSO and 33PATP (8Ci/mM) kinase buffer liquid in carry out.Compound is mixed in reaction vessel with enzyme, and add ATP and substrate mixture startup reaction.After adding 2x stop buffer (20mM) EDTA termination reaction subsequently, the partial confounding compound is put a little on the phosphorylated cotton filter membrane.The sample of point was at room temperature used the 75mM phosphoric acid washing 5-15 minute.Mix with liquid scintillation counter is radiolabeled.
Shi Fan compound is to the IC of Lck in the present invention 50Less than 5 μ M.Preferred compounds of the invention are the selective depressant of Lck.
(comprise and not mentioning here) that treatment has been identified and not yet evaluation aspect the PTKs diseases associated, formula I compound has treatment effectiveness, formula I compound can suppress PTKs.The external model of t cell activation
Behind mitogen or antigen activates, the T cell is by secretion inducing IL-2, and IL-2 is a kind of somatomedin of proliferative phase subsequently of supporting.Therefore, people's IL-2 or the hyperplasia that can measure elementary T-cell or produce as the suitable T-clone of T-cell-stimulating surrogate.In the literature, these two kinds of analyses all described fully and they the existing fully record of parameter (Current Protocols in Immunology, the 2nd volume, 7.10.1-7.11.2.).
Briefly, by can activated T cell with the collaborative cultivation of allotype irritation cell, this be a kind of method that is called unidirectional mixed lymphocyte reacion.According to manufacturer's indication,, refining by Ficoll-Hypaque gradient (Pharmacia) with reactant and stimulator peripheral blood lymphocytes.By using mitomycin c (Sigma) or γ-radiotreatment deactivation irritation cell mitotic division.Reactant and irritation cell according to 2 to 1 ratio, there be or do not had collaborative cultivation the under the condition of test compounds.Generally with 10 5Reactant and 5 * 10 4Stimulator mix and add in microtiter plate (Costar Scientfic) hole at the bottom of the U type (200 μ l volume).Be added with heat-inactivated foetal calf serum (Hyclone Laboratories) or be added with the people AB serum of collecting from male sex blood donor, 5 * 10 -5Culturing cell among the RPMI 1640 of M 2 mercapto ethanol and 0.5%DMSO.In the day before yesterday (being generally three days) of results, with 0.5 μ Ci's 3H thymidine (Amersham) pulse culture.(Betaplate gathers in the crops instrument to the results culture, and Wallac), and (Betaplate Wallac) estimates isotopic absorption to pass through liquid scintillation counter.
By measuring the IL-2 that produces, available same culture systems assessment activated T cells.According to manufacturer's indication, cultivating the beginning back 18 to 24 hours, remove supernatant liquor and pass through the concentration that ELISA (R and d system) measures IL-2.
Available known animal model is directly measured activated T cells or has been proved to be T cell into the effector cell, thus effect in the body of test compounds.The constant portion that has the TXi Baoshouti of mono-clonal anti-CD 3 antibodies (Ab) by connection can swash in vivo T cell.In Model B ALB/c, in bloodletting preceding two hours, intraperitoneal gave anti--CD3Ab of mouse 10 μ g.Resisting-last hour of CD3 Ab, the animal that will be subjected to the reagent thing is with the pre-treatment of single dose compound.Measure the serum level of pro-inflammatory cytokine interferon-(IFN-γ) and tumor necrosis factor-alpha (TNF-α), t cell activation indicator by ELISA.A similar model is to use specific antigens such as keyhole limpet hemocyanin (KLH) to carry out T cell initiation in the body, with identical antigen the lymph-node cell liquid effluent is carried out the external attack second time subsequently.As described before, measure cytokine and produce the state of activation that is used to assess culturing cell.Briefly,, subcutaneously give the C57BL/6 mouse 100 μ g complete Freund's adjuvant emulsive KLH, make its immunity at the 0th day.After the day before yesterday of immunity and immunity first day, second day and the 3rd day are with described compound treatment animal.Gathered in the crops the lymphoglandula liquid effluent at the 4th day, and (be added with heat-inactivated foetal calf serum (Hyclone Laboratories), 5 * 10 at tissue culture medium (TCM) -5The RPMI1640 of M 2 mercapto ethanol and 0.5%DMSO) in, by 6 * 10 6/ ml cultivate they the cell twenty four hours and 48 hours.By the T cell growth factor interleukin II (IL-2) of autocrine and/or the level of IFN-γ in the ELISA assessment culture supernatants.
Also can in the animal model of human diseases, test guiding (lead) compound.By experiment autoimmunity encephalomyelitis (EAE) and collagen protein inductive sacroiliitis (CIA) illustrate.Describe the EAE model of simulating human multiple sclerosis aspect with rat and mouse and (summarized FASEB J.5:2560-2566,1991; The model of mouse: Lab.Invest.4 (3): 278,1981; Rodent models: J.Immunol146 (4): 1163-8,1991).Briefly, the emulsion with myelin basis protein (MBP) or its neuron peptide derivant and CFA makes mouse or rat immunity.Acute illness can add bacteriotoxin such as absordetella pertussis induces generation.Palindromia/alleviate is induced in the adoptive transfer of the T cell by deriving from MBP/ peptide immune animal.
With II collagen type immunity DBA/1 mouse, can induce to produce CIA (J.Immunol:142 (7): 2237-2243).After antigen is attacked, arthritic symptom promptly occurs morning to ten days mouse, and after immunity, can mark in 90 days so long time.In EAE and two kinds of models of CIA, can preventatively give compound or when seizure of disease, give compound.Effectively medicine should be able to reduce severity of disease/or sickness rate.
Can be in mouse allogeneic model test compounds, as dermatoplasty (summary Ann.Rev.Immunol.10:333-58,1992; Transplantation:57 (12): 1701-1706,1994) or heart transplantation (Am.J.Anat.113:273,1963).Briefly, the skin graft of full thickness (full thickness) is transplanted to BALB/c mouse from the C57BL/6 mouse.Check graft every day beginning in the 6th day, collect the evidence that repels.In the neonatal heart transplantation model of mouse, newborn infant's ectocardia of C57BL/6 mouse is transplanted in the auricle of the CBA/J mouse that grows up.Transplant the 4-7 days hearts in back and begin to beat, rejection is carried out visual evaluator thereby observe the termination of beating with dissecting microscope.
By the following embodiment that provides the present invention is described, provides these embodiment only as example.By one or more following method the end product of each embodiment is identified: high performance liquid chromatography (HPLC), ultimate analysis, NMR (Nuclear Magnetic Resonance) spectrum, infrared spectra and high resolution mass spectrum.
Embodiment 1
A) TERTIARY BUTYL AMINE (15ml) is under agitation joined 2-bromo-4 '-metaphenoxy acetophenone (12.7g, according to Tetrahedron Letters.1993, the method in 34,3177, by make 4 '-preparation of metaphenoxy acetophenone bromination) propan-2-ol solution in, in 80 ℃ of these mixtures of heating 3 hours.Mixture is cooled to 0 ℃, and adds concentrated hydrochloric acid (10ml).At room temperature stirred this suspension 18 hours, by solid collected by filtration, obtain 4 '-phenoxy group-uncle's 2-fourth aminoacetophenone hydrochloride (3.75g), m.p.210-212 ℃.
B) (1) with 4 '-phenoxy group-uncle's 2-fourth aminoacetophenone hydrochloride (3.75g) is disposable to join in the sodium ethylate (being prepared by sodium (93mg) is dissolved in the ethanol (50ml)), under 40 ℃, nitrogen environment, stirs this mixture 30 minutes.(2) in another flask, dissolve sodium (331mg) and add propane dinitrile (858mg) with ethanol (50ml).At room temperature stirred this solution 5 minutes, then, (1) step of disposable adding obtains in this solution removed sodium-chlor sedimentary 4 '-phenoxy group-uncle's 2-fourth aminoacetophenone solution.The mixture that generates 50 ℃ of heating 3 hours, then, 80 ℃ of heating 2 hours.Under reduced pressure, remove and desolvate, the oil content of generation is assigned between water and the ethyl acetate.Divide and get organic phase, dry and evaporation obtains black solid.Be dissolved in solid in the hot ethanol and the water grinding, filter and drying, obtain 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-tertiary butyl pyrroles.
C) in the mixture of 180 ℃ of heating 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-tertiary butyl pyrroles (1.9g), methane amide (30ml) and 4-Dimethylamino pyridines (10mg) 6 hours.This mixture is cooled to room temperature and adds entry, the solid that precipitation is dark.Filter and collect this solid, and wash with water, then this solid is boiled in ethanol, filtered while hot is collected insolubles and dry.By preparation property HPLC, on silicagel column, with methylene dichloride/propan-2-ol/ethanol (98: 1: 1) as moving phase, this solid of purifying, obtain the 7-tertiary butyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (4-amino-5-(4-Phenoxyphenyl)-7-tertiary butyl pyrrolo-[2,3-d] phonetic close pyridine), m.p.157-158 ℃. 1HNMR (d 6DMSO) δ 8.15 (1H, s), 7.50-7.35 (4H, m), 7.30 (1H, s), 7.15 (1H, t), 7.10 (4H, m), 6.05 (2H, brs), 1.75 (9H, s).
Embodiment 2
A) under agitation, with 2-bromo-4 '-toluene (150ml) solution of metaphenoxy acetophenone (20.0g) joins in toluene (100ml) solution of Isopropylamine (8.1g), the temperature that keeps reaction mixture simultaneously is below 15 ℃.Stirred this mixture 30 minutes in this temperature, then stirring at room 20 minutes.Filtering mixt is also used the ether debris.Ether (200ml) solution of oxalic acid (10.0g) is added in the filtrate and washing lotion of merging.Filtering mixt obtain 2-isopropylamino-4 '-the metaphenoxy acetophenone oxalate.With the concentrated hydrochloric acid processing oxalate is converted into hydrochloride.Filter and the collection solid salt, be directly used in next step.
B) be suspended in the methyl alcohol (60ml) from the crude product product (3.07g) that a) obtains above-mentioned, and under agitation add propane dinitrile (1.0g).Nitrogen is fed with in the ice-water bath refrigerative suspension, add water (2ml) solution of potassium hydroxide (1.75g) then.After this temperature stirs 15 minutes, extremely boiling of heated mixt under refluxing, and kept boiling state 1 hour, simultaneously nitrogen is fed mixture.With mixture cooling and join in the water (200ml) that feeds nitrogen.Be dissolved in the ether jelly that obtains and separation.With extracted with diethyl ether water layer 2 times, the dry ether layer that merges filters and evaporation, obtains jelly.Under nitrogen, place the curing of spending the night, obtain 2-amino-3-cyano group-1-sec.-propyl-4-(Phenoxyphenyl) pyrroles.
C) will be from b) product (2.75g) that obtains is dissolved in the methane amide (120ml), stirs in 200-205 ℃ of oil bath and heated mixt 2.5 hours, feeds ammonia during this period.Cooling mixture also adds in the frozen water, filters then, obtains beige solid, washes with water.It is found that this solid is product and 4-amino-5-[4-(4-bromine phenoxy group) phenyl of desire preparation]-mixture of 7-sec.-propyl pyrrolo-[2,3-d] pyrimidine.Under nitrogen stirs,, obtain a kind of solid by the method hydrogenated mixture that is similar to described in the embodiment 5 with third-1-alcohol, ammonium formiate and 10% palladium charcoal.By the flash chromatography method on silica gel, make moving phase with ethyl acetate/triethylamine (19: 1), this solid of purifying obtains 7-sec.-propyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.155-156 ℃.
Embodiment 3
A) be dissolved in 4-metaphenoxy acetophenone (150.0g) in the acetate (2L) and, add pyridinium tribromide (251.6g) during this period in batches 50 ℃ of stirrings.This brown solution is joined in the water (3L), and (1 * 800ml is 2 * 400ml) these mixtures then with the toluene extraction.The combining methylbenzene extract, and water and sodium bicarbonate aqueous solution wash successively until no longer bubbling.Separation of methylbenzene extract, dehydration and filtration, and be directly used in following b) step.
B) at nitrogen, stir under, with 1.5 hours with a) go on foot the 2-bromo-4 that obtains '-toluene solution of metaphenoxy acetophenone joins in toluene (1L) solution of cyclopentyl amine (154ml), holding temperature is below 5 ℃ during this period.Stir this mixture 2.5 hours below 10 ℃, and filtering this mixture.Drip concentrated hydrochloric acid (120ml) and handle filtrate, holding temperature is lower than 10 ℃ during this period.Filter and collecting precipitation, grind precipitation, obtain a kind of solid with propan-2-ol/ether (1: 1), 40 ℃ of vacuum-dryings 6.5 hours, obtain 2-encircle penta amino-4 '-the metaphenoxy acetophenone hydrochloride.
C) under nitrogen, in methyl alcohol (500ml) solution of propane dinitrile (9.5g), add b) step product (35.1g).Then, water (75ml) solution with dripping potassium hydroxide (17.0g) in 30 minutes during this period, maintains the temperature between 0-5 ℃.Boiled this mixture 2.5 hours under refluxing.Methyl alcohol (10ml) solution that further adds propane dinitrile (1.0g), and then boiled 3 hours under refluxing.At room temperature placed this mixture 18 hours, methyl alcohol is removed in decompression, and resistates is remained under the nitrogen.Resistates is dissolved in the methylene dichloride (600ml), and water and salt solution washs successively, and is dry then, filter and evaporation obtains a kind of brown solid, grinds this solid with ether, obtain 2-amino-3-cyano group-1-cyclopentyl-4-(4-Phenoxyphenyl) pyrroles, can be directly used in next step.
D) with c) step product (25.9g) be dissolved in methane amide (155ml), N, in the mixing solutions of dinethylformamide (52ml) and formic acid (20.2ml), under nitrogen, heated this mixture 4 hours with 166 ℃ internal temperatures.Make the mixture cooling and, use ethyl acetate (3 * 1500ml) extractions then in its impouring water (3.5L).The acetic acid ethyl acetate extract that merges washes with water, dry then, filter and evaporation, obtain a kind of solid, grind this solid and filtration, obtain a kind of solid with ether, with industrial methanolizing alcohol recrystallization, obtain 7-cyclopentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.178-179 ℃.
Embodiment 4
This embodiment has adopted the method that is similar to embodiment 2 to carry out.Make 2-bromo-4 '-acetonitrile (150ml) solution of phenyl methyl phenyl ketone (25.0g) and TERTIARY BUTYL AMINE (28.4ml) reaction, obtain 4 '-phenyl-uncle's 2-fourth aminoacetophenone hydrobromate (5.31g), m.p.234-237 ℃ (decomposition).Under nitrogen, this compound and propane dinitrile (1.7g) and potassium hydroxide (3.0g) are reacted in methyl alcohol (100ml) solution of water (4ml), obtain 2-amino-4-(4-xenyl)-3-cyano group-1-tertiary butyl pyrroles (3.75g), this product is suspended in the saturated methane amide (200ml) of usefulness ammonia, then, heated this mixture 2 hours at 200-205 ℃, during this period, make ammonia pass through mixture.The cooling back is under nitrogen, mixture is joined in the frozen water (600g), solid collected by filtration, by on silica gel, with ethyl acetate/triethylamine (19: 1) this solid of flash chromatography method purifying as moving phase, obtain 5-(4-the xenyl)-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.212-214 ℃.
Embodiment 5
This embodiment adopts the method that is similar to embodiment 2 to carry out.Make toluene (100ml) solution of neo-pentyl amine (18.4g) and 2-bromo-4 '-toluene (150ml) solution reaction of metaphenoxy acetophenone (33.0g), obtain 2-neo-pentyl-4 '-metaphenoxy acetophenone hydrochloride (13.6g), under nitrogen, itself and potassium hydroxide (7.3g) are reacted in methyl alcohol (200ml) solution of water (10ml) and propane dinitrile (3.2g), obtain 2-amino-3-cyano group-1-neo-pentyl-4-(4-Phenoxyphenyl) pyrroles (6.9g), with this product be dissolved in in the saturated methane amide of ammonia (250ml) and reaction obtain crude product, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/triethylamine (19: 1) as moving phase, obtain product and 4-amino-5-[4-(4-bromine phenoxy group) phenyl of desire preparation]-mixture of 7-neo-pentyl pyrrolo-[2,3-d] pyrimidine.Under nitrogen stirs, by hydrogenation crude product in third-1-alcohol (40ml), ammonium formiate (1.1g) and 10% palladium charcoal (0.3g), thus purified mixture.Filtering mixt.Concentrated filtrate under reduced pressure obtains resistates, and this resistates is dissolved in the hot methanol, cools off then and adds the water induced crystallization.Make the mixture cooling, solid collected by filtration, drying obtain 7-neo-pentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.158-158.5 ℃.
Embodiment 6
This embodiment adopts the method that is similar to embodiment 2 to carry out.At nitrogen, reflux down, with 2-bromo-4 '-thiophenyl methyl phenyl ketone (159.0g), propan-2-ol (400ml) and TERTIARY BUTYL AMINE (100ml) were boiled 18 hours, obtain 4 '-thiophenyl-uncle's 2-fourth aminoacetophenone hydrochloride (74.0g), make propane dinitrile (21.63g) and potassium hydroxide (0.668mol) reaction in itself and the methyl alcohol (2000ml), obtain 2-amino-3-cyano group-4-(4-thiophenyl phenyl)-1-tertiary butyl pyrroles (33.44g), it is dissolved in the methane amide (1100ml), and be heated to 170-180 ℃ 2 hours, make ammonia pass through reaction mixture simultaneously, obtain the 7-tertiary butyl-5-(4-thiophenyl phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.151.5-152.5 ℃.
Embodiment 7
This embodiment adopts the method that is similar to embodiment 3 to carry out.4-(4-methoxyl group phenoxy group) methyl phenyl ketone (50.8g) and the pyridinium tribromide (67.0g) in the acetate (650ml) are reacted, obtain 2-bromo-4 '-(4-methoxyl group phenoxy group) methyl phenyl ketone (80.0g), make TERTIARY BUTYL AMINE (70ml) reaction in itself and the propan-2-ol (250ml), obtain the 2-tertiary butyl-4 '-(4-methoxyl group phenoxy group) methyl phenyl ketone hydrochloride (33.3g), it is dissolved in the methyl alcohol (475ml), and with the reaction of propane dinitrile (9.5g) and potassium hydroxide (16.6g), obtain 2-amino-3-cyano group-4-(4-methoxyl group Phenoxyphenyl)-1-tertiary butyl pyrroles.Be dissolved in this product (20.0g) in the methane amide (650ml) and feed ammonia, during this period, heated these mixtures 2 hours at 190 ℃, by on silica gel, with the flash chromatography method processing of ethyl acetate/triethylamine (19: 1) as moving phase, obtain the 7-tertiary butyl-5-[4-(4-methoxyl group phenoxy group) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.171-172 ℃.
Embodiment 8
A) with being similar to embodiment 10b) method, make 4-chloro-5-iodo-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine (0.57g) and 4-nitrophenyl boric acid (0.30g) (0.126g) catalyzed reaction of two (triphenyl phosphine) palladiums (II) of chlorination, obtain 4-chloro-7-sec.-propyl-5-(4-nitrophenyl) pyrrolo-[2,3-d] pyrimidine, with ammonium chloride (22mg), the mixture of iron powder (0.45g) in water (2ml) and industrial methylated spirit (10ml) reduces this compound, obtain 4-chloro-5-(4-aminophenyl)-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine, make this compound in the container of a sealing with 1, ammonia react in the 4-diox, obtain 4-amino-5-(4-aminophenyl)-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine.
B) under 0 ℃, nitrogen, stirring, to join at the Benzoyl chloride (101mg) in the methylene dichloride (1.0ml) in the mixture of 4-amino-5-(4-aminophenyl)-7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (175mg) in the methylene dichloride (7ml) and triethylamine (73mg).Stirred this mixture 4 hours at 0 ℃, made its temperature rise to room temperature with 1 hour then.Stirring at room reaction mixture 18 hours, add with ice-cooled saturated sodium bicarbonate aqueous solution (10ml) termination reaction then.Divide and get organic layer and use ethyl acetate (3 * 20ml) aqueous layer extracted.The organic layer, drying and the evaporation that wash merging with water obtain lurid solid, by preparation property HPLC purifying, obtain N-(4-{4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } phenyl) benzamide, m.p.192-195 ℃.
Embodiment 9
A) under 20 ℃, nitrogen, stirring, with the 10 minutes acetonitrile with TERTIARY BUTYL AMINE (154ml) (100ml) solution join 2-chloro-4 '-iodobenzene ethyl ketone (158.0g, according to Organic MagneticResonance 12 (12), method preparation described in 1979, the 691-695 pages or leaves) in acetonitrile (700ml) solution.Mixture is warmed to 30 ℃, therefore forms a kind of solution.The exothermic phenomenon of trace takes place then and produce tert-butylamine salt hydrochlorate precipitation.By the cooling of necessity, mixture is remained on below 37 ℃.At room temperature stir this mixture 18 hours, and filtered and use the acetonitrile debris then.Concentrate the filtrate and the washing lotion that merge, make then in its mixture that is dissolved in ether (700ml) and water (500ml).Stir this mixture, regulate pH to 9 with dilute hydrochloric acid simultaneously.Filtering mixt is so that remove the tert-butylamine salt hydrochlorate.With dilute hydrochloric acid acidifying filtrate, obtain 4 '-iodo-uncle 2-fourth aminoacetophenone hydrochloride (102.0g).With the method that is similar to embodiment 2, this product and propane dinitrile (29.9g) and potassium hydroxide (52.3g) are reacted in methyl alcohol (1.5L) and water (100ml), obtain 2-amino-3-cyano group-4-(4-iodophenyl)-1-tertiary butyl pyrroles (63.2g), m.p.166.5-167 ℃.
B) with the method that is similar to embodiment 2, make from the product and methane amide (2L) reaction that a) obtain, make ammonia pass through solution simultaneously, obtain the crude product solid, use the toluene recrystallization, obtain 4-amino-5-(4-iodophenyl)-7-tertiary butyl pyrrolo-[2,3-d] pyrimidine, m.p.188-189 ℃.
C) stir from b) product (600mg) that obtains, 4-acetoamidophenol (828mg), salt of wormwood (702mg), cupric chloride (I) (60mg), oxine (96mg) and N,N-DIMETHYLACETAMIDE (15ml), and under nitrogen, backflow boiling reflux 4 hours.Water (100ml) and ethyl acetate (50ml) are diluted this mixture, and with the sodium hydroxide solution (1ml) of 5M this mixture that alkalizes, filter then.Separating filtrate also washes the dry and evaporation of organic layer with water, obtain resistates, by on silica gel,, obtain N-{4-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group with the flash chromatography method purifying of ethyl acetate as moving phase] phenyl } ethanamide.By 1H NMR confirms structure.Embodiment 10
A) under 0 ℃, nitrogen, stirring, with 4-chloro-5-iodol also [2,3-d] pyrimidine (10.0g sees embodiment 17) join the N of sodium hydride (1.6g is scattered in the mineral oil with 60%) in batches, in dinethylformamide (250ml) suspension.After adding, allow mixture temperature rise to room temperature, when no longer observing the gas generation, drip the N of isopropyl bromide (34.0ml), dinethylformamide (20ml) solution.At room temperature stir this mixture overnight, externally cooling drips water (300ml) termination reaction down then.With ethyl acetate (3 * 300ml) purging compounds.Wash organic layer, drying, filtration and the evaporation of merging with water, obtain 4-chloro-5-iodo-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine, a kind of xanchromatic solid.m.p.116-118℃。By 1H NMR confirms structure.
B) under 105 ℃, nitrogen, heating 4-chloro-5-iodo-7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (2.8g), 4-methoxyphenylboronic acid (1.32g), two (triphenyl phosphine) palladiums (II) of chlorination (625mg), the mixture of toluene (85ml), ethanol (11ml), water (22ml) and sodium bicarbonate (2.2g) 18 hours.Allow mixture be cooled to room temperature, and it is allocated in ethyl acetate (100ml) and the salt solution (100ml).Divide and get organic layer and use ethyl acetate (2 * 50ml) washing water layers.Wash organic layer, drying, filtration and the evaporation under reduced pressure of merging with water, obtain a kind of oily matter of black, the cooling after fixing.By on silica gel, with cyclohexane/ethyl acetate (7: 3) this product of flash chromatography method purifying as moving phase.Merge suitable cut and concentrating under reduced pressure, obtain a kind of xanchromatic oily matter, place and solidify, obtain 4-chloro-7-sec.-propyl-5-(4-p-methoxy-phenyl) pyrrolo-[2,3-d] pyrimidine.By 1H NMR confirms structure.
C) in 120 ℃, pressurized vessel, and heating 4-chloro-7-sec.-propyl-5-(4-p-methoxy-phenyl) pyrrolo-[2,3-d] pyrimidines (1.6g), strong aqua (80ml, S.G.880) and 1, the mixture of 4-diox (80ml) 18 hours.Mixture is cooled to room temperature and under reduced pressure, removes and desolvate, obtain a kind of solid residue, it is allocated between ethyl acetate (100ml) and the water (100ml).Use the ethyl acetate extraction water layer, and wash organic layer, drying, filtration and the evaporation of merging with water, obtain 4-amino-7-sec.-propyl-5-(4-p-methoxy-phenyl) pyrrolo-[2,3-d] pyrimidine.By 1H NMR confirms structure.
D) under-10 ℃, nitrogen, the drips of solution of boron tribromide (the 1M dichloromethane solution of 14.4ml) is added in methylene dichloride (100ml) solution of 4-amino-7-sec.-propyl-5-(4-p-methoxy-phenyl) pyrrolo-[2, the 3-d] pyrimidines (1.35g) that stirring.Allow the temperature of reaction mixture rise to 0 ℃, and stirred 1 hour in this temperature.At-10 ℃, add boron tribromide (the 1M dichloromethane solution of 9.6ml) again, and allow temperature life to 0 ℃, further stirred one hour.Drip saturated sodium hydrogen carbonate solution (50ml) quenching reaction mixture.The mixture placement is spent the night, and isolate dichloromethane layer.Insolubles and drying by the removed by filtration interface obtain 4-amino-5-(4-hydroxy phenyl)-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine.By 1H NMR confirms structure.
E) at 120 ℃ of joltings and heating 4-amino-5-(4-hydroxy phenyl)-7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (0.29g), 2-fluoronitrobenzene (0.15g), salt of wormwood (0.149g) and N, the mixture of dinethylformamide (4.0ml) 5 hours.Under reduced pressure, evaporate this mixture to doing, resistates is allocated between ethyl acetate (30ml) and the water (20ml).Branch gets organic layer and water, diluted sodium hydroxide solution and salt solution wash successively, dewater then, filter and evaporate, obtain a kind of solid, grind this solid with ether, obtain 7-sec.-propyl-5-[4-(2-nitro-phenoxy) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.By 1H NMR confirms structure.
Embodiment 11
At nitrogen, reflux under, boil 7-sec.-propyl-5-[4-(2-nitro-phenoxy) phenyl]-mixture of 7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.15g), ammonium formiate (3 equivalent), 10% palladium charcoal (15mg) and ethanol (5ml) 2 hours.After one hour, further add ammonium formiate (100mg).Cooling mixture also filters by silica.With industrial methylated spirit (2 * 10ml) washing leaching cakes.Evaporated filtrate is also used the ethyl acetate extraction resistates.Decompression is removed ethyl acetate and is obtained resistates, and it by on silica gel, with the flash chromatography method purifying of ethyl acetate as moving phase, is obtained 5-[4-(2-amino-benzene oxygen) phenyl]-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.By 1H NMR confirms structure.
Embodiment 12
Triethylamine (56mg) is joined 4-amino-5-[4-(2-amino-benzene oxygen) phenyl]-anhydrous acetonitrile (5.0ml) solution of 7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (67mg) in, add Acetyl Chloride 98Min. (14.6mg) subsequently.At room temperature stir this mixture one hour, and then be added in the Acetyl Chloride 98Min. (7.3mg) in the anhydrous acetonitrile (0.25ml), and at room temperature stirred this mixture 0.5 hour.Under reduced pressure, mixture is evaporated to dried, and resistates is allocated between water (2ml) and the methylene dichloride (2ml).Pass through Empore The tube filtering mixt is with methylene dichloride (2ml) washing.Divide and get dichloromethane layer and evaporation, obtain N-{2-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } ethanamide.By 1H NMR confirms structure.
Embodiment 13
Reflux down N-{4-[4-(4-amino-7-tertiary butyl pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } mixture boiled 36 hours of ethanamide (1.8g) (with embodiment 9 described methods preparations), industrial methylated spirit (5ml) and hydrazine hydrate (30ml).Make reaction mixture be cooled to room temperature, water (100ml) dilution, with this reaction mixture with ethyl acetate (3 * 50ml) extractions obtain 5-[4-(4-amino-benzene oxygen) phenyl]-the 7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.By 1H NMR confirms structure.
Embodiment 14
Method with similar embodiment 9, under 180 ℃, nitrogen, stir and heating 4-amino-5-(4-iodophenyl)-7-tertiary butyl pyrrolo-[2,3-d] pyrimidine (1.8g), 3-acetoamidophenol (2.48g), salt of wormwood (2.1g), cupric chloride (I) (0.09g), the mixture of oxine (0.15g) and N,N-DIMETHYLACETAMIDE (40ml) 4 hours, obtain N-{3-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } ethanamide.By 1H NMR confirms structure.
Embodiment 15
With N-{3-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } mixture of ethanamide (0.6g), hydrazine hydrate (5ml) and industrial methylated spirit (2ml) heated in vapor bath 2 days.Handle according to embodiment 14 described methods then and obtain resistates, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate as moving phase, obtain 4-amino-5-[4-(3-amino-benzene oxygen) phenyl]-the 7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.By 1H NMR confirms structure.Embodiment 16
Method with similar embodiment 9, with 4-amino-5-(4-iodophenyl)-7-tertiary butyl pyrrolo-[2,3-d] pyrimidine (100mg), salt of wormwood (104mg), N-methyl-(4-kharophen) phenol (120mg), oxine (8mg), cupric chloride (I) are (5mg) and the mixture of N,N-DIMETHYLACETAMIDE (8ml), obtain N-{4-[4-(4-amino-7-tertiary butyl pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl }-the N-methylacetamide.By 1H NMR confirms structure.
Embodiment 17
A) to the N of 4-chlorine pyrrolo-[2, the 3-d] pyrimidine (29.1g, J.Chem.Soc.1960,131) that is stirring, add iodine (52.9g) in dinethylformamide (400ml) solution.(31.9g) adds in the refrigerative mixture in batches with potassium hydroxide pellets, so that the temperature of keeping reaction mixture is about 20 ℃, and in this mixture of stirring at room 2 hours.Add hypo solution (10% aqueous solution 900ml) with stable speed, maintain the temperature at 30 ℃ by exterior cooling.With this mixture of ethyl acetate extraction, the dry extract that merges filters and evaporation under reduced pressure, obtains resistates, it is added in the entry (1L), and (2 * 150ml) extracts with ethyl acetate.Dry acetic acid ethyl ester extract that merges and evaporation obtain solid, make its recrystallization from ethyl acetate.The solid that obtains stirs and filters so that remove some insolubless with methyl alcohol (800ml).Filtrate is evaporated to dried, obtains a kind of light yellow solid, identify that it is 4-chloro-5-iodo-pyrrolo-[2, a 3-d] pyrimidine, m.p.219-221 ℃.
B) under 0 ℃, nitrogen, 4-chloro-5-iodo-pyrrolo-[2,3-d] pyrimidines (5.0g) are added sodium hydride, and (60% is scattered in mineral oil, and N 0.8g) in dinethylformamide (100ml) mixture, allows mixture temperature rise to room temperature then.When stopping release hydrogen, splash into the N of isopropyl bromide (17ml), dinethylformamide (50ml) solution.At room temperature stirred this mixture 20 hours, then water (100ml) termination reaction.Use the ethyl acetate extraction mixture, obtain 4-chloro-5-iodo-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine.
C) under 105 ℃, nitrogen, with two (triphenyl phosphine) palladiums (II) of 4-chloro-5-iodo-7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (0.57g), 4-nitrophenyl boric acid (0.30g), chlorination (0.126g), the mixture heating up of toluene (15ml), ethanol (2ml), water (4ml) and sodium bicarbonate (0.45g) 8 hours.Mixture is cooled to room temperature, it is allocated between salt solution (50ml) and the ethyl acetate (50ml).Further use the ethyl acetate extraction water layer, wash acetic acid ethyl ester extract, dehydration, filtration and the evaporation of merging with water, obtain a kind of solid, with it by on silica gel, with the ethyl acetate of hexanaphthene and incremental change flash chromatography method purifying as moving phase, obtain 4-chloro-7-sec.-propyl-5-(4-nitrophenyl) pyrrolo-[2,3-d] pyrimidine.
D) reflux down the mixture boiled of 4-chloro-7-sec.-propyl-5-(4-nitrophenyl) pyrrolo-[2,3-d] pyrimidines (1.0g), iron powder (1.76g), ammonium chloride (86mg), water (8ml) and industrial methylated spirit (40ml) 1 hour.Filtering mixt and solvent evaporated.Be dissolved in resistates in the ethyl acetate and wash with water.With acetic acid ethyl ester extract dehydration, filtration and evaporation, obtain 5-(4-aminophenyl)-4-chloro-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine.
E) under 0 ℃, nitrogen, stirring, methylene dichloride (5ml) solution of benzene sulfonyl chloride (0.27g) is splashed in methylene dichloride (15ml) solution of 5-(4-aminophenyl)-4-chloro-7-sec.-propyl pyrrolo-[2,3-d] pyrimidines (0.40g) and triethylamine (155mg).Stirred this mixture one hour at 0 ℃, make temperature rise to room temperature then and stirred 18 hours in this temperature.In this mixture, add entry (20ml) and use dichloromethane extraction.Organic layer with the sodium bicarbonate washing merges dewaters then, filters and evaporates, and obtains N-[4-(4-chloro-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] benzsulfamide.
F) in 120 ℃, pressurized vessel, stir under, heating N-[4-(4-chloro-7-sec.-propyl pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] benzsulfamide (0.34g), strong aqua (30ml, SG 0.880) and 1, the mixture of 4-diox (30ml) 16 hours.Allow mixture be cooled to room temperature, and under reduced pressure, remove and desolvate, obtain resistates, it is allocated between water (40ml) and the ethyl acetate (40ml).Divide and get organic layer, water layer is further used ethyl acetate (2 * 40ml) extractions.Acetic acid ethyl ester extract, dehydration, filtration and evaporation that washing merges obtain a kind of solid, and it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/hexanaphthene (8: 2) as moving phase.Collect suitable cut, merge and concentrate, obtain N-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] benzsulfamide, m.p.238-240 ℃.Embodiment 18
At room temperature, the mixture of stirring 4-amino-5-(4-Phenoxyphenyl)-7-tertiary butyl pyrrolo-[2,3-d] pyrimidines (0.20g), N-neoprene imide (80mg) and methylene dichloride (5ml) is 18 hours.Under reduced pressure, concentrate this mixture, and resistates is allocated between ethyl acetate and the water.Divide and get organic layer, dehydration and evaporation, obtain a kind of oily matter, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/triethylamine (95: 5) as moving phase, collect suitable cut, merging and evaporation, obtain the 7-tertiary butyl-6-chloro-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.136.8-137.8 ℃.
Embodiment 19
Under agitation, water (16ml) solution of sodium periodate (0.60g) is added 4-amino-5-[4-(thiophenyl) phenyl]-glacial acetic acid (30ml) solution of 7-tertiary butyl pyrrolo-[2,3-d] pyrimidines (1.0g) in, keep temperature to be lower than 5 ℃ simultaneously.At room temperature stirred this mixture 66 hours.Filtering mixt also adds water (300ml) in filtrate.With solid sodium bicarbonate this mixture that alkalizes, remove by filter a spot of solid, filtrate is used ethyl acetate extraction, obtain resistates, it by on silica gel, with the flash chromatography method purifying of ethyl acetate/triethylamine (9: 1) as moving phase, is obtained a kind of solid, under similarity condition, repeat chromatography, obtain the 7-tertiary butyl-5-(4-phenylsulfinyl phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.180-182 ℃.
Embodiment 20
Peroxide one vitriolate of tartar (potassium peroxymonosulphate) water (10ml) solution (4.93g) is under agitation splashed into 4-amino-5-[4-(thiophenyl) phenyl]-7-tertiary butyl pyrrolo-[2,3-d] in the methyl alcohol (5ml) and glacial acetic acid (5ml) solution of pyrimidine (1.0g), keep temperature to be lower than 5 ℃ simultaneously.At room temperature stirred this mixture 3 hours, water (50ml) dilution then.With this mixture of ethyl acetate extraction, obtain a kind of solid, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/triethylamine (9: 1) as moving phase, merge suitable cut and concentrated, obtain a kind of solid, grind this solid, obtain the 7-tertiary butyl-5-(4-phenyl sulfonyl-phenyl)-7H-pyrrolo-[2 with sherwood oil (boiling point is 60-80 ℃), 3-d] pyrimidine-4-base amine, m.p.222-224 ℃.
Embodiment 21a and 21b
Under refluxing, with the 7-tertiary butyl-4-amino-5-[4-(4-methoxyl group phenoxy group) phenyl]-7H-pyrrolo-[2,3-d] mixture boiled 1 hour of hydrobromic acid aqueous solution (25ml) of pyrimidine-4-base amine (1.1g, embodiment 7), glacial acetic acid (25ml) and 48% (w/v).Allow mixture be cooled to room temperature, be added to then in frozen water and the ethyl acetate.Stir this mixture, add excessive solid sodium bicarbonate simultaneously lentamente.Divide and to get ethyl acetate layer, wash with water, dewater and evaporate, obtain a kind of solid residue, with it by on silica gel, with the methyl alcohol of ethyl acetate/triethylamine (19: 1) and incremental change flash chromatography method purifying as moving phase.Collect suitable cut, merging and evaporation, obtain 4-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolopyrimidine-5-yl) phenoxy group] phenol (m.p.254-255 ℃) (embodiment 21a) and 4-[4-(4-amino-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenol (m.p.304-305 ℃) (embodiment 21b).
Embodiment 22
Under refluxing, with 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.50g), ethylene carbonate (ethylene carbonate) (0.16g), N, the mixture boiled of the sodium hydroxide powder of dinethylformamide (20ml) and catalytic amount 1 hour.This mixture of evaporation under reduced pressure, and water (30ml) grinding residues.Filter this mixture, obtain a kind of solid, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/industrial methylated spirit (9: 1) as moving phase, obtain 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanol, m.p.144.5-145 ℃.
Embodiment 23
Under room temperature, nitrogen, stirring, (60% is scattered in the mineral oil, 60mg) adds the anhydrous N of 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (302mg), in dinethylformamide (20ml) solution with sodium hydride.At room temperature stirred this mixture 30 minutes, and added cyclopentene oxide (200mg) then, heated these mixtures 3 hours, then 170 ℃ of heating 1 hour at 150 ℃.Under reduced pressure, concentrate this mixture and water grinding residues, filter, obtain a kind of solid.By on silica gel, with ethyl acetate/industrial methylated spirit (9: 1) this solid of flash chromatography method purifying as moving phase, obtain 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentanol, m.p.162-162.5 ℃ (behind the methanol recrystallization).
Embodiment 24
Under nitrogen, in the ice/water-bath, stir 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] mixture of pyrimidine-4-base amine (600mg) and four (triphenyl phosphine) palladium (40ml) and anhydrous dimethyl sulfoxide (DMSO) (30ml), then, under 0 ℃, nitrogen, add tetrahydrofuran (THF) (10ml) solution of cyclopentadiene one epoxy compounds (200mg) through syringe.At room temperature stirred this mixture 66 hours, and under reduced pressure, removed tetrahydrofuran (THF) then and in resistates, add water.Mixture was left standstill 18 hours, use ethyl acetate extraction then, obtain a kind of resistates, it is passed through on silica gel, with the flash chromatography method purifying of ethyl acetate/industrial methylated spirit (9: 1) as moving phase, obtain 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-2-enol, be a kind of oily matter.By 1H NMR and mass spectrum confirm structure.
Embodiment 25
Under normal pressure, in the ethanol (20ml), make catalyzer with 10% palladium charcoal (50mg), with gaseous hydrogen hydrogenation 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-2-enol (110mg).By removed by filtration catalyzer and evaporated filtrate, obtain 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentanol, be a kind of oily matter.By 1H NMR and mass spectrum confirm structure.
Embodiment 26
At room temperature, stir 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-2-enol (188mg), 4-methylmorpholine-mixture of N-oxide compound (63mg) in tetrahydrofuran (THF) (5ml) 10 minutes.In mixture, add perosmic anhydride (the t-butanol solution 0.42ml of 2.5%w/v).At room temperature stirred this mixture 3 hours, then directly on silica gel, carry out the flash chromatography method as moving phase with ethyl acetate/industrial methylated spirit (9: 1), obtain 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-1,2, the 3-triol is a kind of oily matter.By 1H NMR and mass spectrum confirm structure.
Embodiment 27
A) under nitrogen, stir 4-chloro-7-cyclopentyl-5-iodol also [2,3-d] pyrimidine (1.26g) and 2-Phenoxyphenyl three potassium fluoborate (1.0g, by being similar at J.Org.Chem.1995, method described in the 60:3020-3027, make butyllithium in 2-phenoxy group bromobenzene and the tetrahydrofuran (THF)-70 ℃ of reactions, subsequently with boric acid (IV) triisopropyl ester, obtain with the potassium bifluoride prepared in reaction subsequently) the degassing toluene (40ml), mixture in ethanol (10ml) and the water (10ml), add two (triphenyl phosphine) palladiums (II) of chlorination (0.25g), add sodium bicarbonate (2.0g) subsequently.Stir and heated this mixture 16 hours at 105 ℃, be cooled to room temperature then.Separating mixture and evaporation under reduced pressure upper strata, obtain resistates, it is passed through on silica gel, with the flash chromatography method purifying of petroleum ether/ethyl ether (2: 1) as moving phase, obtain 4-chloro-7-cyclopentyl-5-(2-Phenoxyphenyl) pyrrolo-[2,3-d] pyrimidine, can be directly used in next step of this embodiment.
B) in 120 ℃, pressurized vessel, stir and the product (0.79g), 1 of heating 4-diox (60ml) and concentrated ammonia solution (60ml, mixture S.G.0.880) 18 hours from a) obtaining.This mixture of evaporation under reduced pressure, and resistates is allocated between water and the ethyl acetate.Divide and get organic layer, dehydration and evaporation, obtain a kind of jelly, make the crystallization in methyl alcohol of this jelly, obtain 7-cyclopentyl-5-(2-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.109-110 ℃.
Embodiment 28
Except initial raw material was 3-phenoxy group bromobenzene, this embodiment had adopted the method for similar embodiment 27 to carry out, and obtained 4-cyclopentyl-5-(3-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.127.5-128 ℃.
Embodiment 29
A) under 0-2 ℃, be stirred in the 2-phenyl-1 in the anhydrous pyridine (20ml), 3-diox-3-alcohol (4.89g), the while under agitation splashes into anhydrous pyridine (80ml) solution of new purified 4-toluene sulfonyl chloride (5.9g), keeps temperature to be lower than 2 ℃ during this period.Stirred this mixture 100 minutes at 2 ℃, add then in the entry (500ml).Discard liquid and the gum of remnants is dissolved in the ether, dehydration and evaporation obtain resistates, with the crystallization in methyl alcohol of this resistates, obtain 2-phenyl-1,3-diox-3-base-4-tosylate, m.p.125.3-125.9 ℃.
B) under nitrogen, stir sodium hydride 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] and pyrimidine hydrogen bromate (0.6g), sodium hydride (60% is scattered in the mineral oil, 80mg) and anhydrous N, and the mixture of dinethylformamide (30ml) 30 minutes.Add 4-tosylate (0.76g) that a) step obtains and in 145 ℃ of these mixtures of heating 16 hours.Under reduced pressure, remove and desolvate, and in resistates, add water.Filter this mixture, obtain solid, by on silica gel, with ethyl acetate/industrial methylated spirit (9: 1) this solid of flash chromatography method purifying as moving phase, obtain 5-(4-Phenoxyphenyl)-7-(2-phenyl-1,3-diox-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.By 1H NMR and mass spectrum confirm structure.
Embodiment 30
In 5-(4-Phenoxyphenyl)-7-(2-phenyl-1,3-diox-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (170mg), add dilute hydrochloric acid (solution of 45ml 2M), and under refluxing, boil this mixture.Add third-1-alcohol (30ml) and boiled this mixture 6 hours under refluxing, propyl alcohol is removed in distillation then.The evaporation under reduced pressure mixture obtains resistates, grinds this resistates and filter with ethyl acetate to obtain solid, be dissolved in it in methyl alcohol and pass through purification by chromatography, obtain 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1, the 3-glycol.By 1H NMR and mass spectrum confirm structure.
Embodiment 31
A) under room temperature, nitrogen, stirring, (60% is scattered in the mineral oil, 0.28g) adds the anhydrous N of 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidines (1.96g), in dinethylformamide (40ml) solution with sodium hydride.Stir this mixture then 30 minutes and dripped allyl bromide 98 (0.62ml).After 1 hour, add allyl bromide 98 (0.20ml) at this mixture of stirring at room again, at room temperature stirred this mixture then 18 hours.Under agitation this mixture is added in the entry, filters the solid and the drying of collecting precipitation, obtain 4-chloro-5-iodo-7-(third-1-alkene-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine, can be directly used in b) step.
B) will be dissolved in the tetrahydrofuran (THF) (50ml) from a) going on foot the product (2.05g) that obtains, and at room temperature stir with 4-methylmorpholine N-oxide compound (850mg).The t-butanol solution (the solution 5ml of 2.5%w/v) that adds perosmic anhydride then.Left standstill this mixture 18 hours, evaporation under reduced pressure obtains solid then, this solid is dissolved in toluene/propan-2-ol (2: 1), and filtered while hot and evaporated filtrate obtain 3-[4-chloro-5-iodo-7H-pyrrolo-[2 then, 3-d] pyrimidin-7-yl] the third-1, the 2-glycol.
C) under nitrogen, stirring is from b) mixture of the ethanol (25ml) of the product (1.90g), 4-Phenoxyphenyl boric acid (1.14g) that the step obtains, the toluene (100ml) of the degassing, the degassing, the water (25ml) of the degassing, then, add two (triphenyl phosphine) palladiums (II) of chlorination (0.40g), add sodium bicarbonate (2.0g) subsequently.Under refluxing, stirring, boiled this mixture 18 hours.With this mixture according to embodiment 10b) method described handles, obtain a kind of oily matter, by on silica gel, with ethyl acetate/industrial methylated spirit (9: 1) this oily matter of flash chromatography method purifying as moving phase, obtain 3-[4-chloro-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1, the 2-glycol.
D) with 3-[4-chloro-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1,2-glycol (0.6g) is dissolved in 1, in the 4-diox (60ml), and the adding strong aqua (60ml, S.G.0.880).In 120 ℃, pressurized vessel, stir and heated this mixture 18 hours.This mixture of evaporation under reduced pressure obtains resistates, and this resistates is allocated between water and the ethyl acetate.Branch is got ethyl acetate layer and is washed with water, dewater then and evaporate, obtain resistates, by on silica gel, with ethyl acetate/industrial methylated spirit (9: 1) this resistates of flash chromatography method purifying as moving phase, obtain 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1, the 2-glycol.By 1H NMR and mass spectrum confirm structure.
Embodiment 32
A) with the method that is similar to embodiment 17b,, make 4-chloro-5-iodo-7H-pyrrolo-[2 at 0 ℃, 3-d] pyrimidine and N, the sodium hydride reaction in the dinethylformamide is reacted with bromocyclopentane then, obtain also [2,3-d] pyrimidine of 4-chloro-7-cyclopentyl-5-iodol after treatment.
B) with 2,4,4, the 6-tetrabromobisphenol, 5-cyclohexadiene-1-ketone makes 2-anisidine bromination, obtains 4-bromo-2-anisidine, makes the tert-Butyl dicarbonate reaction in this product and the tetrahydrofuran (THF) so that protect amino.At-78 ℃, handle described product with butyllithium, handle with trimethyltin chloride then, obtain 4-tert-butoxycarbonyl amino-3-p-methoxy-phenyl trimethylammonium stannane (staunane).
C) under 65 ℃, nitrogen, stirring,, under triphenylarsine (1.07g) in the dinethylformamide (100ml) and three (dibenzalacetones), two palladiums (O) existence (0.65g), make a) product (4.91g) and b) product (5.45g) reaction 18 hours at N.Mixture is cooled to room temperature, and adds in the entry.With this mixture of ethyl acetate extraction, obtain a kind of oily matter, by on silica gel, with the ethyl acetate of cyclohexane/ethyl acetate (19: 1) and increasing amount gradually this oily matter of flash chromatography method purifying as moving phase, obtain 4-chloro-7-cyclopentyl-4-(4-tert-butoxycarbonyl amino-3-p-methoxy-phenyl)-pyrrolo-[2,3-d] pyrimidine, be a kind of solid.
D) under 0 ℃, c in methylene dichloride (150ml)) trifluoroacetic acid (15ml) reaction in product (3.58g) and the methylene dichloride (50ml), obtain 5-(4-amino-3-p-methoxy-phenyl)-4-chloro-7-cyclopentyl pyrrolo-[2,3-d] pyrimidine after the processing, be a kind of oily matter.
E) make d) product (0.5g) and Benzoyl chloride reaction, obtain N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl behind the chromatography] benzamide.By 1HNMR and mass spectrum confirm structure.
F) in 120 ℃, pressurized vessel, make e) product (0.42g) and 1, strong aqua (30ml in the 4-diox (30ml), S.G.0.880) reaction, behind the treated and chromatography, obtain N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzamide.By 1H NMR and mass spectrum confirm structure.
Embodiment 33
Under-10 ℃, nitrogen stir, the dichloromethane solution (the 1M solution of 0.9ml) of boron tribromide is splashed into product N-[4-(the 4-amino-7-cyclopentyl-7H-pyrrolo-[2 of embodiment 32,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] in methylene dichloride (6ml) solution of benzamide (130mg), after adding, make mixture temperature rise to 0 ℃ and stirred 1.5 hours at 0 ℃.At 0 ℃, drip saturated sodium hydrogen carbonate solution (5ml) quenching reaction mixture.There is the temperature of exothermic phenomenon and mixture to rise to 10 ℃.Make mixture temperature rise to room temperature,, obtain N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl then with this mixture of dichloromethane extraction] benzamide, m.p.173-175 ℃ (decomposition).By 1H NMR and mass spectrum confirm structure.
Embodiment 34
At 0 ℃, make 5-(4-amino-3-p-methoxy-phenyl)-4-chloro-7-cyclopentyl pyrrolo-[2,3-d] pyrimidine (0.50g is prepared with the method that is similar to embodiment 32) and the reaction of the benzene sulfonyl chloride (0.31g) in pyridine (5ml) and methylene dichloride (1ml).With the method that is similar to embodiment 32, make and handle product and the ammonia react that the back is obtained, obtain N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzsulfamide, m.p.113-115 ℃.By 1H NMR and mass spectrum confirm structure.
Embodiment 35
With the method that is similar to embodiment 33, under-10 ℃, make N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] boron tribromide reaction in benzsulfamide and the methylene dichloride, obtain N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-hydroxy phenyl] benzsulfamide, m.p.265-267 ℃.By 1H NMR and mass spectrum confirm structure.
Embodiment 36a and 36b
With the method that is similar to embodiment 34 and 35, by N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl]-4-tert.-butylbenzene sulphonamide (embodiment 36b) beginning, preparation N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-hydroxy phenyl]-4-tert.-butylbenzene sulphonamide, m.p.278-280 ℃ (embodiment 36a).
Embodiment 37
A) with being similar to embodiment 17c) method, make 4-chloro-5-iodo-7-cyclopentyl pyrrolo-[2,3-d] pyrimidine (1.80g) and the reaction of 4-(2-methoxyl group phenoxy group) phenyl-boron dihydroxide, obtain 4-chloro-7-cyclopentyl-5-[4-(2-methoxyl group) Phenoxyphenyl] pyrrolo-[2,3-d] pyrimidine.
B) in 120 ℃, pressurized vessel, make product (1.2g) and 1 a), the ammoniacal liquor in the 4-diox (50ml, S.G.0.880) reaction obtains 7-cyclopentyl-5-[4-(2-methoxyl group phenoxy group) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.
Embodiment 38a and 38b
With the method that is similar to embodiment 33, by 7-cyclopentyl-5-[4-(2-methoxyl group) Phenoxyphenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (embodiment 38b) beginning, preparation 2-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenol (embodiment 38a), m.p.107-109 ℃.Embodiment 39
With the method that is similar to embodiment 33, preparation N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl]-the 4-chlorobenzamide.
Embodiment 40
With the method that is similar to embodiment 18, make 7-cyclopentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] N-neoprene imide (0.90g) reaction in pyrimidine-4-base amine semihydrate (2.5g) and the methylene dichloride (80ml), obtain 6-chloro-7-cyclopentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.
Embodiment 41
At nitrogen, reflux under, with the mixture boiled of 4-amino-5-(4-Phenoxyphenyl)-7-tertiary butyl pyrrolo-[2,3-d] pyrimidines (5.8g), Glacial acetic acid (55ml) and Hydrogen bromide (48% solution of 55ml) 18 hours.Cooling mixture, and pass through solid collected by filtration.Wash this solid successively with methyl alcohol and ether, obtain 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine hydrogen bromate, m.p.288-292 ℃.With this product and diluted sodium hydroxide solution (100ml 5%w/v solution) with ethanol (60ml) is warm and remove ethanol by distillation, make hydrobromate transform into free alkali by under agitation.Cooling mixture also passes through solid collected by filtration, and this solid of water thorough washing obtains 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 42-48 (universal method)
With Gilson 215 liquid automatic samplers, in the mixture of fluorobenzene in the diaphragm seal pipe (1.25 molar equivalent) and salt of wormwood (2 molar equivalent), add 4-amino-5-(4-hydroxy phenyl)-7-sec.-propyl pyrrolo-[2,3-d] N of pyrimidine (1 molar equivalent), dinethylformamide solution (6g is dissolved in 240ml) (as a kind of stock solution).At 120 ℃, reacting by heating mixture 4 hours and 140 ℃ of further heating 1 hour under the jolting is evaporated to dried then in a centrifugal evaporator.
Reaction residue is dissolved in ethyl acetate/triethylamine (1ml) (9: 1) also by a silica post (3g SiO 2: 12mm diameter * 20mm height), with 9: 1 ethyl acetate/triethylamine (4 * 2ml) wash-outs.The post elutriant that evaporation merges obtains waxy solid, greasy dirt or expansible spumescence product.Amount of reagent
Embodiment number Fluorobenzene (mg) K 2CO 3(mg) The volume of phenol solution
?42 N-(2-fluoro-5-nitrophenyl) ethanamide (91.5mg) 102mg ?3960μl
?43 5-fluoro-2-nitrobenzoic acid (88.6mg) 106mg ?4105μl
?44 2-fluoro-5-nitrobenzoic acid (84mg) 100mg ?3892μl
?45 5-fluoro-2-Nitroanisole (80mg) 103mg ?3934μl
?46 4-fluoro-3-nitrobenzoic acid methyl esters (60mg) 67mg ?2593μl
?47 4-chloro-2-fluoronitrobenzene (86mg) 103mg ?3994μl
?48 2,2-dimethyl-2 '-fluoro-5 '-nitro (N-propionanilide) is (63.5mg) 59mg ?2267μl
Output/LCMS
Embodiment ?MF ?Mwt Record M + ％HPLC Output (mg)
?42 ?C 23H 22N 6O 4 ?446.17 Be 78.9 ?150mg
?43 ?C 22H 19N 5O 5 ?433.139 Be 78.2 ?96.8mg
?44 ?C 22H 19N 5O 5 ?433.139 Be 62.6 ?64.5mg
?45 ?C 22H 21N 5O 4 ?419.444 Be 74.9 ?140.3mg
?46 ?C 23H 21N 5O 5 ?447.454 Be 74.2 ?94.2mg
?47 ?C 21H 18ClN 5O 3 ?423.843 Be 80.9 ?175.3mg
?48 ?C 26H 28N 6O 4 ?488.550 Be 86.4 ?16.4mg
The prepared compound of embodiment 42-48 is:
Embodiment 42N-{2-[4-(amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrophenyl } ethanamide;
Embodiment 435-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 2-nitrobenzoic acid; Embodiment 442-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrobenzoic acid;
Embodiment 457-sec.-propyl-5-[4-(3-methoxyl group-4-nitrophenoxy) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine;
Embodiment 464-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-3-nitrobenzoic acid methyl esters;
Embodiment 475-[4-(5-chloro-2-nitro-phenoxy) phenyl]-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine;
Embodiment 48N-{2-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrophenyl }-2,2-dimethyl propylene acid amides;
Embodiment A
By following description the purposes of The compounds of this invention in medicinal compositions is produced has been described.In this is described, term " active compound " expression any one compound of the present invention, particularly any one end product of (but particularly) previous embodiment.A) capsule
In preparation during capsule, with the lactose disaggregation of the active compound of 10 parts of weight and 240 parts of weight and mix.This mixture is packed in the hard gelatin capsule, and every capsules contains a unitary dose or part unit dose of active compound.B) tablet
Prepare tablet with following ingredients:
Weight part active compound 10 lactose 190 W-Gums 22 Povidones 10 Magnesium Stearates 3
With active compound, lactose and partial starch disaggregation and mix, with the ethanolic soln of Povidone with the granulating mixture that obtains.Dry granules is mixed with Magnesium Stearate and remaining starch.Pressing mixt on tabletting machine obtains tablet, and every contains a unitary dose or part unit dose of active compound.C) ECT
By at aforementioned b) described in method prepare tablet.Adopt conventional method, with the ethanol of 20% Cellacefate and 3% diethyl phthalate: methylene dichloride (1: 1) solution carries out enteric coating to slice, thin piece.D) suppository
In preparation during suppository, the active compound of 100 parts of weight is mixed with the triglyceride level suppository base of 1300 parts of weight, and make this mixture forming prepare suppository, every suppository contains the treatment effective amount of actives.

Claims (27)

1. the formula I compound that comprises its pharmacy acceptable salt:
Figure C9880515200021
R wherein 1Be hydrogen, 2-phenyl-1,3-diox-5-base, C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group or be (optional replace phenyl) C 1-6Alkyl, wherein said alkyl, cycloalkyl and cycloalkenyl group are optional by one or more OR AGroup replaces, wherein R ABe hydrogen or C 1-6Alkyl, condition are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, halo, hydroxyl, (the optional phenyl that replaces) C 1-6Alkyl, optional phenyl or the R that replaces 4And R 3Be formula (a)
Figure C9880515200022
Wherein said phenyl ring is also optional to be substituted, and A is NH, O, NHSO 2, SO 2NH, C 1-4Alkylidene chain, NHCO, NHCO 2, CONH, NHCONH, CO 2Or S (O) pWherein p is 0,1 or 2, or A does not exist and R 5Be directly connected on the phenyl ring; And R 5Be the optional phenyl that replaces, in addition when A does not exist, R 5For a) by the optional phthalimido that replaces of halo, or b) the pyrazoles ring is by one or more hydroxyls or the optional pyrazolyl amino that replaces of the optional phenyl that replaces; R 4For being selected from the heterocyclic group of thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, indazolyl, each of these heterocyclic groups is optional to be replaced by one or more following groups: C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, hydroxyl, the optional phenyl that replaces, (the optional phenyl that replaces) C 1-6Alkyl, (the optional phenyl that replaces) C 1-6Alkylthio or (the optional phenyl that replaces) C 1-6Alkoxyl group; Wherein said term " the optional phenyl that replaces " means the optional phenyl that is replaced by one or more following groups: a) C 1-6Alkyl, b) C 1-6Alkoxyl group, c) phenoxy group, d) hydroxyl, e) phenyl C 1-6Alkyl, f) halo, g) formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, (C 1-6Alkoxyl group) carbonyl, 5-hydroxyl-1-phenyl-3-pyrazolyl or optional by C 1-6Alkyl, C 1-6The benzoyl that alkoxyl group or halo replace, h) formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition, i) by the optional phthalimido that replaces of halo, j) described phenyl ring is benzo-fused formation naphthyl or k) nitro.
2. according to the compound of claim 1, R wherein 1Be C 1-6Alkyl, C 3-8Cycloalkyl or be (optional replace phenyl) C 1-6Alkyl, wherein said alkyl and cycloalkyl are optional by one or more formula OR AGroup replaces, R ABe hydrogen or C 1-6Alkyl, condition are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, halo, hydroxyl, (the optional phenyl that replaces) C 1-6Alkyl, optional phenyl or the R that replaces 4And R 3Be formula (a)
Figure C9880515200031
Wherein said phenyl ring is also optional to be substituted and A is NH, O, NHSO 2, SO 2NH, C 1-4Alkylidene chain, NHCO, NHCO 2, CONH, NHCONH, CO 2Or S (O) pWherein p is 0,1 or 2, or A does not exist and R 5Be directly connected on the phenyl ring; And R 5Be the optional phenyl that replaces, in addition when A does not exist, R 5For a) by the optional phthalimido group that replaces of halo, or b) the pyrazoles ring is by one or more hydroxyls or the optional pyrazolyl amino that replaces of the optional phenyl that replaces; R 4For being selected from the heterocyclic group of thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, indazolyl, each of these heterocyclic groups is optional to be replaced by one or more following groups: C 1-6Alkyl, C 3-6Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, hydroxyl, the optional phenyl that replaces, (the optional phenyl that replaces) C 1-6Alkyl, (the optional phenyl that replaces) C 1-6Alkylthio or (the optional phenyl that replaces) C 1-6Alkoxyl group; Wherein said term " the optional phenyl that replaces " means by the optional phenyl that replaces of one or more following groups: a) C 1-6Alkyl, b) C 1-6Alkoxyl group, c) phenoxy group, d) hydroxyl, e) phenyl C 1-6Alkyl, f) halo, g) formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, (C 1-6Alkoxyl group) carbonyl, 5-hydroxyl-1-phenyl-3-pyrazolyl or by C 1-6Alkyl, C 1-6The optional benzoyl that replaces of alkoxyl group or halo, h) formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition, i) optional phthalimido or the j that is replaced by halo) described phenyl ring is benzo-fused formation naphthyl.
3. according to the compound of claim 1, R wherein 1Be C 3-6Alkyl, C 3-8Cycloalkyl or C 5-7Cycloalkenyl group, wherein said alkyl, cycloalkyl and cycloalkenyl group are optional to be replaced by one or more hydroxyls, and condition is on the carbon atom that hydroxyl can not be positioned at nitrogen is connected.
4. according to the compound of claim 1, R wherein 1Be sec.-propyl, the tertiary butyl, 2-hydroxyethyl, cyclopentyl, neo-pentyl, 2-hydroxycyclopent base, 4-hydroxycyclopent-2-thiazolinyl, 3-hydroxycyclopent base, 2,3,4-trihydroxy-cyclopentyl, 1,3-dihydroxyl third-2-base or 2,3-dihydroxypropyl.
5. according to the compound of claim 1, R wherein 2Be hydrogen or halo.
6. according to the compound of claim 1, R wherein 2Be hydrogen or chlorine.
7. according to the compound of claim 1, R wherein 3Be formula (a) group,
Figure C9880515200041
Wherein said phenyl ring is also optional to be substituted, and
A is O, NHSO 2, NHCO or S (O) pWherein p is 0,1 or 2, and R 5Be the optional phenyl that replaces.
8. according to the compound of claim 1, wherein A is NHSO 2
9. according to the compound of claim 1, wherein A is NHCO.
10. according to the compound of claim 1, wherein A is O or S.
11. according to the compound of claim 1, wherein A is O.
12. according to the compound of claim 1, wherein R 3Be the 2-Phenoxyphenyl; the 3-Phenoxyphenyl; the 4-Phenoxyphenyl; 4-(thiophenyl)-phenyl; 4-(4-methoxyl group phenoxy group) phenyl; 4-(phenyl-sulfinyl) phenyl; 4-(phenyl-alkylsulfonyl) phenyl; 4-(4-hydroxyphenoxy) phenyl; 4-phenylsulfonamido phenyl; 4-benzamido phenyl; 4-(4-kharophen phenoxy group) phenyl; 4-(2-nitro-phenoxy) phenyl; 4-(4-amino-benzene oxygen) phenyl; 4-(3-amino-benzene oxygen) phenyl; 4-(2-amino-benzene oxygen) phenyl; 4-(3-kharophen phenoxy group) phenyl; 4-[4-(N-methyl kharophen) phenoxy group] phenyl; 4-(2-kharophen phenoxy group) phenyl; 4-(2-acetylaminohydroxyphenylarsonic acid 4-nitrophenoxy) phenyl; 4-(3-carboxyl-4-nitrophenoxy) phenyl; 4-(2-carboxyl-4-nitrophenoxy) phenyl; 4-(4-trifluoromethyl-2-nitro-phenoxy) phenyl; 4-benzamido-3-p-methoxy-phenyl; 4-benzamido-3-hydroxy phenyl; 4-phenylsulfonamido-3-p-methoxy-phenyl; 4-phenylsulfonamido-3-hydroxy phenyl; 3-hydroxyl-4-(4-tert.-butylbenzene sulfonamido) phenyl; 4-(2-hydroxyphenoxy) phenyl; 4-(4-chlorobenzoyl amino)-3-hydroxy phenyl; 4-(3-methoxyl group-4-nitrophenoxy) phenyl; 4-(4-methoxycarbonyl-2-nitro-phenoxy) phenyl; 4-(4-carboxyl-2-nitro-phenoxy) phenyl; 4-(5-chloro-2-nitro-phenoxy) phenyl or 4-[4-nitro-2-(2,2-dimethyl propylene amido) phenoxy group] phenyl.
13. according to the compound of claim 1 or 2, wherein
R 1Be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, benzyl or 2-hydroxyethyl;
R 2Be hydrogen, methyl, halo, hydroxyl or phenyl; And
R 3Be the 2-Phenoxyphenyl, the 3-Phenoxyphenyl, the 4-Phenoxyphenyl, 4-(4-chloro-N-phthalimido)-3-tolyl, 3-chloro-4-(3-chlorophenoxy) phenyl, 4-(4-methylamino-phenylamino) phenyl, 4-(4-methylamino-phenylamino)-2-p-methoxy-phenyl, 4-(4-methylamino-benzyl) phenyl, 4-anilino-2-p-methoxy-phenyl, 3-hydroxyl-4-(4-toluyl amino) phenyl, 3-hydroxyl-4-(2-methoxybenzoyl amino) phenyl, 4-(4-chlorobenzoyl amino)-3-hydroxy phenyl, 3-hydroxyl-4-(2-naphthalene sulfonyl amino) phenyl, 3-hydroxyl-4-(4-tert.-butylbenzene sulfonamido) phenyl, 4-[N-(5-hydroxyl-1-phenylpyrazole-3-yl) amino] phenyl or 4-phenyloxycarbonyl amino-3-hydroxy base.
14. the formula I compound according to claim 1 can be represented with formula Ib and pharmacy acceptable salt thereof: R wherein 1Be hydrogen, C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group or be (optional replace phenyl) C 1-6Alkyl, wherein said alkyl, cycloalkyl, cycloalkenyl group are chosen wantonly by one or more formula OR AGroup replaces, R ABe hydrogen or C 1-6Alkyl, condition are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected; R 2Be hydrogen or halo; R xBe C 1-6Alkyl, C 1-4Alkoxyl group, halo or hydroxyl; R yBe C 1-6Alkyl, C 1-4Alkoxyl group, halo, hydroxyl, nitro or formula NR 10R 11Group, wherein R 10And R 11Independent is hydrogen, C 1-6Alkyl, phenyl, C 1-6Alkanoyl, C 1-6Alkoxy carbonyl or R yBe formula-COR 9Group, wherein R 9Be hydroxyl, C 1-6Alkoxyl group, phenoxy group or formula NR 10R 11Group, wherein R 10And R 11As preceding definition; And m and n independently are 0,1 or 2.
15. according to the compound of claim 14, wherein
R 1Be C 1-6Alkyl, C 3-8Cycloalkyl, C 5-7Cycloalkenyl group, wherein said alkyl, cycloalkyl, cycloalkenyl group are chosen wantonly by one or more formula OR AGroup replaces, wherein R ABe hydrogen or C 1-6Alkyl, condition are formula OR AOn the carbon atom that group can not be positioned at nitrogen is connected.
16. compound according to claim 14, wherein R1 is sec.-propyl, the tertiary butyl, 2-hydroxyethyl, cyclopentyl, neo-pentyl, 2-hydroxycyclopent base, 4-hydroxycyclopent-2-thiazolinyl, 3-hydroxycyclopent base, 2,3,4-trihydroxy-cyclopentyl, 1,3-dihydroxyl third-2-base or 2, the 3-dihydroxypropyl.
17. according to the compound of claim 14, wherein R 2Be hydrogen or chlorine.
18. according to the compound of claim 14, wherein R xBe hydroxyl or C 1-4Alkoxyl group.
19. according to the compound of claim 14, wherein R yBe C 1-4Alkyl, C 1-4Alkoxyl group, nitro, kharophen, amino, N-methyl kharophen, carboxyl, hydroxyl or halo.
20. according to the compound of claim 14, wherein m is 0 or 1.
21. according to the compound of claim 20, wherein m is 0.
22. according to the compound of claim 14, wherein n is 0 or 1.
23. according to each compound among the claim 14-22, wherein n is 0 or 1, and R yBe hydroxyl, amino or kharophen.
24. according to formula (I) compound of claim 1, wherein this compound is to be selected from following compound or its pharmacy acceptable salt:
The 7-tertiary butyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
The 7-tertiary butyl-6-chloro-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
7-sec.-propyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
7-cyclopentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-(4-the xenyl)-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
7-neo-pentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
The 7-tertiary butyl-5-(4-(thiophenyl) phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
The 7-tertiary butyl-5-[4-(4-methoxyl group phenoxy group) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
The 7-tertiary butyl-5-[4-(benzenesulfinyl) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
The 7-tertiary butyl-5-(4-benzenesulfonyl phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
N-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] benzsulfamide
N-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] benzamide
N-{4-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } ethanamide
7-sec.-propyl-5-[4-(2-nitro-phenoxy) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-[4-(4-amino-benzene oxygen) phenyl]-the 7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-[4-(3-amino-benzene oxygen) phenyl]-the 7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-[4-(2-amino-benzene oxygen) phenyl]-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
N-{3-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } ethanamide
N-{4-[4-(the 4-amino-7-tertiary butyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl }-the N-methylacetamide
N-{2-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl } ethanamide
N-{2-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrophenyl } ethanamide
5-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 2-nitrobenzoic acid
2-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrobenzoic acid
2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanol
2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentanol
4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-2-enol
6-chloro-7-cyclopentyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-(4-Phenoxyphenyl)-7-(2-phenyl-1,3-diox-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentanol
4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ring penta-1,2, the 3-triol
7-cyclopentyl-5-(2-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
7-cyclopentyl-5-(3-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine 4-base amine
2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1, the 3-glycol
3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the third-1, the 2-glycol
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzamide
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl] benzamide
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzsulfamide
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl] benzsulfamide
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl]-4-tert.-butylbenzene sulphonamide
2-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenol
7-sec.-propyl-5-[4-(3-methoxyl group-4-nitrophenoxy) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
4-[4-(4-amino-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-3-nitrobenzoic acid methyl esters
4-[4-(4-amino-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenol
7-cyclopentyl-5-[4-(2-methoxyl group phenoxy group) phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-hydroxy phenyl]-the 4-chlorobenzamide
5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
5-[4-(5-chloro-2-nitro-phenoxy) phenyl]-7-sec.-propyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
N-{2-[4-(4-amino-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-the 5-nitrophenyl }-2,2-dimethyl propylene acid amides
25. medicinal compositions, it contains each described formula I compound and salt and pharmaceutically acceptable diluent or carrier among the claim 1-24 that treats significant quantity.
26. each described formula I compound is used for the treatment of purposes in the medicine of proliferative disease and/or disease of immune system in production among the claim 1-24.
27. the method for the formula I compound shown in being prepared as follows,
Figure C9880515200101
R in the formula 1, R 2And R 3Definition such as claim 1 described in,
This method comprises:
A) 50-250 ℃, choose wantonly in the presence of a kind of catalyzer, make formula II compound as follows and methane amide condensation
R in the formula 1, R 2And R 3Definition such as claim 1 described in; Perhaps
B) make formula V compound as follows and ammonia or the reaction of a kind of ammonium salt at 15-250 ℃
Figure C9880515200112
R in the formula 1, R 2And R 3Definition such as claim 1 described in, and Y is a leavings group; Perhaps
C) make R in formula VIII compound as follows and the formula 5Definition such as the formula R described in the claim 1 5The reaction of OH compound
Figure C9880515200113
R in the formula 1, R 2And R 3Definition according to claim 1 and X is a halogen atom
And obtain R in the formula 3Represent AR 5Formula I compound, at AR 5A represents O and R in the group 5Definition such as claim 1 described in; Perhaps
D) make R in formula IX compound as follows and the formula 5Definition such as claim 1 described in and X is the formula R of halogen atom 5The reaction of X compound,
Figure C9880515200121
R in the formula 1And R 2Definition such as claim 1 described in
And obtain R in the formula 3Represent AR 5Formula I compound, at AR 5A is O and R in the group 5Definition such as claim 1 described in.
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